Conditions: Differentiated Thyroid Cancer
Keywords: Selumetinib, Differentiated Thyroid Cancer , AZD6244
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 233
Healthy volunteers: no

Brief summary:
The study is designed to evaluate the clinical efficacy, safety and tolerability of selumetinib with radioactive iodine therapy in patients with differentiated thyroid cancer.

Detailed description:
A Randomised, Double Blind Study to Compare the Complete Remission Rate Following a 5-Week Course of Selumetinib or Placebo and Single Dose Adjuvant Radioactive Iodine Therapy in Patients with Differentiated Thyroid Cancer.

Arms:
arm 1: Selumetinib plus Radioactive Iodine Therapy arm 2: Placebo plus Radioactive Iodine Therapy

Interventions: intervention 1: Selumetinib intervention 2: Placebo intervention 3: Radioactive Iodine Therapy
Intervention descriptions: intervention 1: 3 capsules of 25 mg strength orally twice a day for approximately 5 weeks treatment period intervention 2: 3 capsules ( to match Selumetinib capsules) orally twice a day for approximately 5 weeks treatment period intervention 3: A single oral radioactive iodine dose of 100 mCI(3.7 GBq) 131I (+/-10% at the time of administration)to be administered 30 days after randomization. Additionaly, Thyrogen (Recombinant human TSH) will be used to stimulate iodine uptake according to the manufacturer's recommendation(0.9 mg intramuscular injection once a day for the 2 days prior to the dose of radioactive iodine)

Protocol document:
Prot_000.pdf: 
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Clinical Study Protocol Amendment 
 
Amendment Number 
1 
 
Drug Substance 
Selumetinib (AZD6244) 
 
Study Code 
D1532C00065 
 
Date 
3 April 2013 
 
Protocol Dated 
24 January 2013 
 
 
 
 
 
 
 
 
 
 
A Randomised, Double Blind Study to Compare the Complete Remission 
Rate Following a 5-Week Course of Selumetinib or Placebo and Single Dose 
Adjuvant Radioactive Iodine Therapy in Patients with Differentiated 
Thyroid Cancer 
 
 
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
Sponsor: 
AstraZeneca AB, 151 85 Södertälje, Sweden 
Centres affected by the Amendment: 
This protocol amendment affects all the centres participating in this study. 
The protocol for the study is to be amended as follows:  
Section of protocol affected: 
Study Plan Table 3


Clinical Study Protocol Amendment 1 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 3 April 2013 
2(13) 
Previous text: 
Table 3 
Study Plan (Note, only rows with changes are shown) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Visit Description 
Screening 
Randomi
sation 
On -
treatment 
safety 
visit 
Thyrogen 
RAI 
therapy 
Last day 
of 
treatment 
30 days 
post 
treatment 
4 Month 
safety 
follow up 
9 
Month 
FU 
Primary 
endpoint 
assessmentsa 
27 
Month 
safety 
follow up 
3 Year 
FU 
Protocol 
Section 
Timing 
Day  
-28 to –1 
Day 1 
Day 14 
Days  
29 & 30 
Day 31 
 Day 36 
Week 10 
4 months 
post visit 
5 
9 
months 
post 
visit 5 
18 months 
post visit 5 
27 
months 
post visit 
5 
3 years 
post 
visit 5 
 
Visit Window 
N/A 
N/A 
±1wk 
N/A 
N/A 
N/A 
± 2 days 
± 2 
weeks 
± 3 
months 
Refer to 
Table 4 
± 2 
months 
± 1 
month 
 
Physical examination 
X 
 
X 
 
 
 
X 
 
 
 
 
 
6.5.6 
Plasma/serum sample for 
exploratory analysisb 
 
X 
 
 
 
 
 
 
 
 
 
 
6.10.2 
Optional genetic consent & 
sample (whole blood)  
 
X 
 
 
 
 
 
 
 
 
 
 
6.9 
Vital signs (including height 
at screening), weight 
X 
X 
 
 
 
 
X 
 
 
 
 
 
6.5.8 
Clinical chemistry 
X 
 
X 
 
 
 
X 
 
 
 
 
 
6.5.5 
Haematology 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
6.5.5 
ECGe 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
6.5.7.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO/MUGAf 
X 
 
 
 
 
 
 
 
 
 
 
 
6.5.7.1 
Ophthalmologic 
examinationf 
X 
 
 
 
 
 
 
 
 
 
 
 
6.5.9.2 


Clinical Study Protocol Amendment 1 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 3 April 2013 
3(13) 
Table 3 
Study Plan (Note, only rows with changes are shown) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Visit Description 
Screening 
Randomi
sation 
On -
treatment 
safety 
visit 
Thyrogen 
RAI 
therapy 
Last day 
of 
treatment 
30 days 
post 
treatment 
4 Month 
safety 
follow up 
9 
Month 
FU 
Primary 
endpoint 
assessmentsa 
27 
Month 
safety 
follow up 
3 Year 
FU 
Protocol 
Section 
Timing 
Day  
-28 to –1 
Day 1 
Day 14 
Days  
29 & 30 
Day 31 
 Day 36 
Week 10 
4 months 
post visit 
5 
9 
months 
post 
visit 5 
18 months 
post visit 5 
27 
months 
post visit 
5 
3 years 
post 
visit 5 
 
Visit Window 
N/A 
N/A 
±1wk 
N/A 
N/A 
N/A 
± 2 days 
± 2 
weeks 
± 3 
months 
Refer to 
Table 4 
± 2 
months 
± 1 
month 
 
PK blood samplesh 
 
X 
 
X 
 
 
 
 
 
 
 
 
6.7 
Thyrogen injection 
 
 
 
Xx2 
 
 
 
 
 
Xx2a 
 
 
5.5.4.1 
Tumour biopsy on 
progression (optional) 
Optional sample on disease progression (for example, if the patient is re-treated for persistent or recurrent thyroid cancer, or has further surgery). 
6.10.3 
b Provision of these samples is mandatory in this study.  
f  These assessments must be performed during the screening period, and then only on symptomatology according to the relevant protocol section. 


Clinical Study Protocol Amendment 1 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 3 April 2013 
4(13) 
Revised text: 
Table 3 
Study Plan (Note, only rows with changes are shown) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Visit Description 
Screening 
Randomi
sation 
On -
treatment 
safety 
visit 
Thyrogen 
RAI 
therapy 
Last day 
of 
treatment 
30 days 
post 
treatment 
4 Month 
safety 
follow up 
9 
Month 
FU 
Primary 
endpoint 
assessmentsa 
27 
Month 
safety 
follow up 
3 Year 
FU 
Protocol 
Section 
Timing 
Day  
-28 to –1 
Day 1 
Day 14 
Days  
29 & 30 
Day 31 
 Day 36 
Week 10 
4 months 
post visit 
5 
9 
months 
post 
visit 5 
18 months 
post visit 5 
27 
months 
post visit 
5 
3 years 
post 
visit 5 
 
Visit Window 
N/A 
N/A 
±1wk 
N/A 
N/A 
N/A 
± 2 days 
± 2 
weeks 
± 3 
months 
Refer to 
Table 4 
± 2 
months 
± 1 
month 
 
Physical examination 
X 
 
X 
X 
(Day 29 
or 30) 
 
 
X 
 
 
 
 
 
6.5.6 
Plasma/serum sample for 
exploratory analysisb 
 
X (pre-
dose) 
 
 
 
 
 
 
 
 
 
 
6.10.2 
Optional genetic consent & 
sample (whole blood)  
 
X (pre-
dose) 
 
 
 
 
 
 
 
 
 
 
6.9 
Vital signs (including height 
at screening), weight 
X 
X (pre-
dose) 
X 
X 
(Day 29 
or 30) 
 
 
X 
 
 
 
 
 
6.5.8 
Clinical chemistry 
X 
X (pre-
dose) 
X 
X 
(Day 29 
or 30) 
 
 
X 
 
 
 
 
 
6.5.5 
Haematology 
X 
X (pre-
dose) 
X 
X 
(Day 29 
or 30) 
 
 
X 
 
 
X 
 
X 
6.5.5 
ECGe 
X 
X 
 
Xe (Day 
29 or 30) 
 
 
X 
 
 
 
 
 
6.5.7.2 


Clinical Study Protocol Amendment 1 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 3 April 2013 
5(13) 
Table 3 
Study Plan (Note, only rows with changes are shown) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Visit Description 
Screening 
Randomi
sation 
On -
treatment 
safety 
visit 
Thyrogen 
RAI 
therapy 
Last day 
of 
treatment 
30 days 
post 
treatment 
4 Month 
safety 
follow up 
9 
Month 
FU 
Primary 
endpoint 
assessmentsa 
27 
Month 
safety 
follow up 
3 Year 
FU 
Protocol 
Section 
Timing 
Day  
-28 to –1 
Day 1 
Day 14 
Days  
29 & 30 
Day 31 
 Day 36 
Week 10 
4 months 
post visit 
5 
9 
months 
post 
visit 5 
18 months 
post visit 5 
27 
months 
post visit 
5 
3 years 
post 
visit 5 
 
Visit Window 
N/A 
N/A 
±1wk 
N/A 
N/A 
N/A 
± 2 days 
± 2 
weeks 
± 3 
months 
Refer to 
Table 4 
± 2 
months 
± 1 
month 
 
ECHO/MUGAf 
X 
 
 
 
 
 
X 
 
 
 
 
 
6.5.7.1 
Ophthalmologic 
examinationf 
X 
 
 
 
 
 
X 
 
 
 
 
 
6.5.9.2 
PK blood samplesh 
 
X 
 
Xh (Day 
29 or 30) 
 
 
 
 
 
 
 
 
6.7 
Thyrogen injection 
 
 
 
Xx2 
(Day 29 
and 30) 
 
 
 
 
 
Xx2a 
 
 
5.5.4.1 
Tumour biopsy on 
progression (optional) 
Optional sample on disease progression (for example, if the patient is re-treated for persistent or recurrent thyroid cancer, or has further surgery). 
Note that both a plasma and serum sample for exploratory analysis should also be taken on disease progression. 
6.10.3 
6.10.2 
b Provision of these samples is mandatory in this study. Samples should also be obtained on progression (refer to Section 6.10.2). 
f These assessments must also be performed on symptomatology according to the relevant protocol section. 


Clinical Study Protocol Amendment 1 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 3 April 2013 
6(13) 
 
Reason for Amendment:  
FDA strongly recommends adding additional safety assessments to the protocol: 
x
Clinical chemistry and haematology assessments on Day 30  
x
A focused physical examination on Day 30 
x
Collection of vital signs (except height) on Day 14, and 30 
x
An ophthalmologic examination (including slit lamp examination) and 
echocardiogram or MUGA scan at the Week 10 visit to allow a comparison with 
baseline in all patients. 
AstraZeneca added further clarification: 
x
Day 1 samples should be taken pre-dose as indicated. 
x
Clinical chemistry and haematology added on Day 1. 
x
Clarification of sample requirements for Day 29 and/or 30. 
x
Clarification of requirements for progression plasma/serum sample for exploratory 
biomarkers. 
Section of protocol affected: 
Table 9 
Volume of blood to be drawn from each patient 


Clinical Study Protocol Amendment 1 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 3 April 2013 
7(13) 
Previous text: 
Table 1 
Volume of blood to be drawn from each patient  
Assessment 
Maximum 
sample 
volume a 
(mL) 
Typical 
number of 
samples (over 
18+ months) 
Total volume 
(mL) 
Safety 
Clinical chemistry (local analysis) 
5 
3 
15 
 
Haematology (local analysis) 
3 
5 
15 
Efficacy 
Tg, TSH, TgAb (central analysis) 
10 
4 
40 
PK 
2 
8 
16 
Genetics at randomisation (optional) 
10 
1 
10 
Exploratory biomarkers at randomisation, serum  
10 
1 
10 
Exploratory biomarkers at randomisation, plasma  
10 
1 
10 
Exploratory biomarkers on progression, serum  
10 
1 
10 
Exploratory biomarkers on progression, plasma  
10 
1 
10 
Total
 
 
136 
Revised text: 
Table 2 
Volume of blood to be drawn from each patient  
Assessment 
Maximum 
sample 
volume a 
(mL) 
Typical 
number of 
samples (over 
18+ months) 
Total volume 
(mL) 
Safety 
Clinical chemistry (local analysis) 
5 
5 
25 
 
Haematology (local analysis) 
3 
7 
21 
Efficacy 
Tg, TSH, TgAb (central analysis) 
10 
4 
40 
PK 
2 
8 
16 
Genetics at randomisation (optional) 
10 
1 
10 
Exploratory biomarkers at randomisation, serum  
10 
1 
10 
Exploratory biomarkers at randomisation, plasma  
10 
1 
10 
Exploratory biomarkers on progression, serum  
10 
1 
10 
Exploratory biomarkers on progression, plasma  
10 
1 
10 
Total
 
 
152 
 
Reason for Amendment: 
Additional clinical chemistry and haematology assessments at FDA request. 


Clinical Study Protocol Amendment 1 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 3 April 2013 
8(13) 
Section of protocol affected: 
Table 4: Study Plan for the 18 month Primary Endpoint Assessments 
Previous text: 
Clinical chemistry/haematology (required for Stage 1) 
Revised text: 
Haematology (required for Stage 1) 
Reason for Amendment:  
Clarification by AstraZeneca to make consistent with Table 3. Only haematology is required 
at Visit 10 (18 months post-RAI dose). 
Section of protocol affected: 
Inclusion criteria 13 
Previous text: 
Male patients with sexual partners who are pregnant or who could become pregnant (ie, 
women of child-bearing potential) must agree to use acceptable methods of contraception for 
12 weeks after completing study therapy, or longer if required for standard RAI administration 
restrictions and in accordance with local labels, to avoid pregnancy and/or potential adverse 
effects. 
Revised text: 
Male patients with sexual partners who are pregnant or who could become pregnant (ie, 
women of child-bearing potential) must agree to use acceptable methods of contraception 
until 12 weeks after completing study therapy, or longer if required for standard RAI 
administration restrictions and in accordance with local labels, to avoid pregnancy and/or 
potential adverse effects. 
Reason for Amendment:  
Clarification to the inclusion criterion 13 by AstraZeneca. 
Section of protocol affected: 
Exclusion criteria 2 
Previous text: 
Diagnosis of anaplastic thyroid cancer, medullary thyroid cancer, or Hürthle cell carcinoma 
(refer to inclusion criterion 3 for further details on Hürthle cell eligibility). 


Clinical Study Protocol Amendment 1 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 3 April 2013 
9(13) 
Revised text: 
Diagnosis of anaplastic thyroid cancer, medullary thyroid cancer, or Hürthle cell carcinoma 
(refer to inclusion criterion 4 for further details on Hürthle cell eligibility). 
Reason for Amendment:  
Correction to the cross reference by AstraZeneca (administrative change). 
Section of protocol affected: 
6.4.3 Blood sample assessments for efficacy 
Previous text: 
Investigators may also perform local biochemical analysis for these parameters as per standard 
site practice if desired, however this data will not be used for study-related decision making. If 
local analysis is performed, the data may be collected by eCRF for the clinical study database, 
and Investigators must ensure that the maximum permissible blood volumes for individual 
patients at their institutions are not exceeded. 
Revised text: 
Investigators may also perform local biochemical analysis for these parameters as per standard 
site practice if desired, however this data will not be used for study-related decision making. If 
local analysis is performed, Investigators must ensure that the maximum permissible blood 
volumes for individual patients at their institutions are not exceeded. 
Reason for Amendment:  
Clarification to data collection plans by AstraZeneca. 
Section of protocol affected: 
6.4.4.2 Whole body diagnostic 131I nuclear medicine scan (WBS) 
Previous text: 
WBS definition of structural DTC 
Any patient with increased 131I uptake considered not to be anatomically normal (where 
normal includes uptake in the salivary glands, stomach, gastrointestinal, urinary tract and 
bladder), that is  biologically consistent with DTC will be classified as not in complete 
remission for the primary endpoint of this study (due to having RAI-avid structural DTC). 
For the thyroid bed, < 0.1% uptake on the region-of-interest method drawn over the thyroid 
bed will be considered normal/negative (no disease). If uptake in the thyroid bed is  0.1% 
then these patients will be deemed not to be in remission due to the presence of RAI-avid 
disease. 


Clinical Study Protocol Amendment 1 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 3 April 2013 
10(13) 
Note that if an abnormality identified by US in stage 1, is subsequently shown to be RAI 
avid/positive on WBS in stage 2, the WBS data takes precedent over a negative biopsy/FNA 
from the same area. 
The WBS evaluation will be made by blinded, independent central review. 
Revised text: 
WBS definition of structural DTC 
The WBS evaluation will be made by blinded, independent central review. 
If the central review determines no visible 131I uptake then the WBS for that patient will 
be considered normal/negative (no disease).  Areas considered to be anatomically normal 
(for example uptake in the salivary glands, stomach, gastrointestinal, urinary tract and 
bladder) will not be considered disease. 
If the central review determines there is a low level of visible uptake in the thyroid bed: 
x
Uptake must be < 0.1% to be considered normal/negative (no disease). 
x
If uptake in the thyroid bed region is  0.1%, the patient will be deemed not to 
be in remission due to the presence of iodine-avid DTC. 
The % uptake in the thyroid bed (using the region-of-interest method drawn over the 
thyroid bed) will be measured and calculated by the local Investigator site and entered 
into the eCRF, to be made available to the central reviewer. 
If an abnormality identified by US  is subsequently shown to be RAI avid on WBS, the WBS 
data takes precedent over a negative biopsy/FNA. 
Reason for Amendment:  
Clarification to the WBS central review process by AstraZeneca. 
Section of protocol affected: 
6.4.4.3 Neck MRI and 6.4.4.4 Chest CT 
Previous text: 
Post-operative (screening) 
This baseline assessment is performed to determine study eligibility according to criterion 6 in 
Section 4.1).  The baseline post-operative images will be available at the central imaging CRO 
to aid interpretation of the primary endpoint image central read if necessary (refer to Section 
6.3). 


Clinical Study Protocol Amendment 1 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 3 April 2013 
11(13) 
Revised text: 
This baseline assessment is performed to determine study eligibility according to Section 4.1.  
The baseline post-operative images will be available at the central imaging CRO to aid 
interpretation of the primary endpoint image central read if necessary (refer to Section 6.3). 
Reason for Amendment:  
Correction of cross-reference by AstraZeneca (administrative change). 
Section of protocol affected: 
6.5.3 Recording of adverse events 
Previous text: 
N/A 
Revised text: 
All adverse events will be graded according to NCI CTCAE Version 4. 
Reason for Amendment:  
Clarification at FDA request. 
Section of protocol affected: 
6.5.3 Adverse event variables 
Previous text: 
Variables 
The following variables will be collected for each AE (note, only criteria with changes are 
shown): 
x
Maximum CTCAE grade 
x
AE caused patient’s withdrawal from study (yes or no) 
Revised text: 
The following variables will be collected for each AE (note, only criteria with changes are 
shown): 
x
CTCAE grade information 
x
AE caused patient’s withdrawal from study treatment 


Clinical Study Protocol Amendment 1 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 3 April 2013 
12(13) 
Reason for Amendment:  
Clarification to data collection by AstraZeneca (CTCAE grade changes will be collected in the 
eCRF). 
Section of protocol affected: 
6.5.5 Laboratory safety Assessment 
Previous text: 
Blood and urine samples for determination of clinical chemistry, haematology and urinalysis 
will be taken at the times indicated in the Study Plan (Table 3). 
Revised text: 
Blood and urine samples for determination of clinical chemistry, haematology and urinalysis 
will be taken at the times indicated in the Study Plan (Table 3). For samples taken after Day 
1 during the study treatment period, the sample may be taken any time of day (ie, it does 
not matter whether it is pre-dose or post-dose). Day 1 samples should be taken pre-dose. 
Reason for Amendment:  
Clarification of sampling times by AstraZeneca. 
Section of protocol affected: 
6.5.7.1 ECHO or MUGA and 6.5.9.2 Ophthalmologic examination 
Previous text: 
These assessments will be conducted at screening. 
Revised text: 
These assessments will be conducted at the timepoints indicated in the Study Plan (Table 
3). 
Reason for Amendment:  
To ensure consistency with addition of Week 10 assessments at FDA request. 
Section of protocol affected: 
6.10.1 BRAF and NRAS patient population 
Previous text: 
Archival tumour sample from every patient will be analysed for BRAF and NRAS mutational 
status centrally using standardised methodology. Full analytical methodology details will be 
provided in the CSR. 


Clinical Study Protocol Amendment 1 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 3 April 2013 
13(13) 
The genetic analysis of archival tumour samples to identify the BRAF and NRAS patient 
population will be performed retrospectively in the study (after randomisation but prior to the 
primary endpoint data analysis). 
Revised text: 
Archival tumour sample from every patient will be analysed for BRAF and NRAS mutational 
status centrally using standardised methodology. Full analytical methodology details will be 
provided in the CSR. 
The genetic analysis of archival tumour samples to identify the BRAF and NRAS patient 
population will be performed retrospectively in the study (after randomisation but prior to the 
primary endpoint data analysis). 
BRAF/NRAS positive = mutations in BRAF/NRAS have been detected 
BRAF/NRAS negative =  no mutation in BRAF/NRAS has been detected   
BRAF/NRAS unknown = mutation status in BRAF/NRAS cannot be confirmed 
Reason for Amendment:  
Clarification of BRAF/NRAS mutation status definitions by AstraZeneca 
Section of protocol affected: 
6.10.1.1 Archival tumour sample 
Previous text: 
- 
20 pre-cut sections from formalin-fixed paraffin-embedded tumour tissue block, 
presented on slides, including one stained with haematoxylin and eosin.  Each section is to be 
5 ȝm thick. 
Revised text: 
- 
20 pre-cut sections from formalin-fixed paraffin-embedded tumour tissue block, 
presented on slides. Each section is to be 5 ȝm thick. 
Reason for Amendment: 
Haematoxylin and eosin stained sections will be prepared by the AstraZeneca appointed 
central laboratory in order to ensure sample processing consistency for all samples received as 
part of the study. 
Persons who initiated the Amendment: 
AstraZeneca at FDA request. 
 


 
 
Clinical Study Protocol Amendment No 1 
Appendix A 
 
Drug Substance 
Selumetinib (AZD6244)
 
Study Code 
D1532C00065 
 
Edition Number 
1 
 
Date 
3 April 2013 
 
Protocol Dated 
24 January 2013 
 
 
 
 
 
 
 
 
 
Appendix A 
Signatures 
 


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Clinical Study Protocol Amendment  
 
Amendment Number 
2 
 
Drug Substance 
Selumetinib (AZD6244) 
 
Study Code 
D1532C00065 
 
Date 
15 July 2013 
 
Protocol Dated 
24 January 2013 
 
 
 
 
 
 
 
 
 
 
A Randomised, Double Blind Study to Compare the Complete Remission 
Rate Following a 5-Week Course of Selumetinib or Placebo and Single Dose 
Adjuvant Radioactive Iodine Therapy in Patients with Differentiated 
Thyrod Cancer 
 
 
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
 
Sponsor: 
AstraZeneca AB, 151 85 Södertälje, Sweden   
Centres affected by the Amendment: 
This protocol amendment affects all the centres participating in this study. 
The protocol for the study is to be amended as follows:  
 
Section of protocol affected: 
Protocol Synopsis and section 2. Study Objectives  
Previous text: 
2.1           Primary objectives 
x
To compare the efficacy of selumetinib with radioactive iodine therapy (RAI), 
versus placebo with RAI, by assessment of complete remission rate at 18 months 


Clinical Study Protocol Amendment 2 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 15 July 2013 
2(17) 
post RAI treatment in the overall study population. Complete remission is defined 
in Section 6.4.1. 
x
To compare the efficacy of selumetinib with RAI, versus placebo with RAI, by 
assessment of complete remission rate at 18 months post RAI treatment in a sub-
group of patients with tumours known to be mutation positive for BRAF or NRAS 
(defined in Section 6.10.1). Complete remission is defined in Section 6.4.1. 
2.2           Secondary objectives 
1. 
To compare the efficacy of selumetinib with RAI, versus placebo with RAI by 
assessment of clinical remission rate at 18 months post RAI treatment in the overall 
study population. Clinical remission is defined in Section 6.4.6. 
2. 
To compare the efficacy of selumetinib with RAI, versus placebo with RAI by 
assessment of clinical remission rate at 18 months post RAI treatment in a sub-
group of patients with tumours known to be mutation positive for BRAF or NRAS 
(defined in Section 6.10.1). Clinical remission is defined in Section 6.4.6. 
3. 
To assess the safety and tolerability of selumetinib with RAI compared to placebo 
with RAI. 
4. 
To investigate the pharmacokinetics (PK) of selumetinib and N-desmethyl 
selumetinib when administered to patients with differentiated thyroid cancer. 
Revised text: 
2.1           Primary objective 
To compare the efficacy of selumetinib with radioactive iodine therapy (RAI), versus placebo 
with RAI, by assessment of complete remission rate at 18 months post RAI treatment in the 
intention to treat (ITT) study population. Complete remission is defined in Section 6.4.1. 
2.2           Secondary objectives 
1. 
To compare the efficacy of selumetinib with RAI, versus placebo with RAI, by 
assessment of complete remission rate at 18 months post RAI treatment in a 
sub-group of patients with tumours known to be mutation positive for BRAF 
or NRAS (defined in Section 6.10.1). Complete remission is defined in Section 
6.4.1. 
2. 
To compare the efficacy of selumetinib with RAI, versus placebo with RAI by 
assessment of clinical remission rate at 18 months post RAI treatment in the ITT 
study population. Clinical remission is defined in Section 6.4.6. 
3. 
To compare the efficacy of selumetinib with RAI, versus placebo with RAI by 
assessment of clinical remission rate at 18 months post RAI treatment in a sub-


Clinical Study Protocol Amendment 2 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 15 July 2013 
3(17) 
group of patients with tumours known to be mutation positive for BRAF or NRAS 
(defined in Section 6.10.1). Clinical remission is defined in Section 6.4.6. 
4. 
To assess the safety and tolerability of selumetinib with RAI compared to placebo 
with RAI. 
5. 
To investigate the pharmacokinetics (PK) of selumetinib and N-desmethyl 
selumetinib when administered to patients with differentiated thyroid cancer. 
Reason for Amendment:  
FDA comments. Efficacy in the genetic sub-group population of BRAF or NRAS mutation 
positive patients will be considered a secondary objective (rather than co-primary). 
Terminology clarification for the overall study population; now defined as the intention to 
treat (ITT) population.  
 
Section of protocol affected: 
Protocol Synopsis, Statistical methods 
Previous text: 
Approximately 228 patients will be randomised in a 2:1 ratio in this study. The primary 
analysis will be performed when patients have been followed for 18 months following their 
RAI treatment. There will be two primary analysis populations: the first will comprise all 
randomised patients (overall population); the second will comprise the sub-group of 
randomised patients with tumours known to be mutation positive for BRAF or NRAS.  The 
primary endpoint of complete remission rate will be analyzed using a logistic regression 
model with covariates histology status (papillary, follicular, poorly differentiated), mutation 
status (overall population only, BRAF/NRAS positive, BRAF/NRAS negative) and age, 
provided there are enough data points for a meaningful analysis. There will be two primary 
analysis populations: the first will comprise all randomised patients; the second will comprise 
the sub-group of randomised patients with tumours known to be mutation positive for BRAF 
or NRAS. To control the type I error rate for the study and account for the correlation between 
the two primary endpoints, the Dunnett and Tamhane step-up procedure will be used. The 
correlation between the primary endpoint comparisons will be calculated as w, where w is 
the proportion of the overall population who are in the mutation positive sub-group. The 
associated significance level for declaring statistical significance in the mutation positive sub-
group adjusting for this correlation to maintain an overall 5% type I error rate whilst assigning 
4% to the overall population will then be derived. 
Assuming the true complete remission rates in the overall study population are 30% and 50% 
for the placebo and selumetinib-containing arms, respectively, the study will have 80% power 
to demonstrate a statistically significant difference at the 4% (2-sided) significance level.  


Clinical Study Protocol Amendment 2 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 15 July 2013 
4(17) 
Assuming the true complete remission rates in the mutation-positive sub-group are 30% and 
62% for the placebo and selumetinib-containing arms, respectively, the study will have 80% 
power to demonstrate a statistically significant difference at the 1% (2-sided) significance 
level.  
All secondary endpoints will be analysed at the time of the primary analysis. Exploratory 
biomarker analysis may be analysed after the time of the primary analysis and reported 
separately to the CSR (apart from the somatic genetic data required for analysis of the second 
primary endpoint). 
All randomised patients will continue to be followed until the final study visit (3 years after 
their RAI treatment). At this time, data on clinical status, incidence of re-treatment and long-
term safety will be summarised. 
Revised text: 
Approximately 228 patients will be randomised in a 2:1 ratio in this study. The primary 
analysis will be performed when patients have been followed for 18 months following their 
RAI treatment. The primary analysis population will comprise all randomised patients 
(ITT population) and the primary endpoint of complete remission rate at 18 months will 
be analyzed using a logistic regression model including treatment as the only covariate. 
Results will be presented in terms of the odds ratio, 95% confidence interval and 
associated p-value. Logistic regression modelling including treatment and covariates 
histology status, mutation status and age, will be performed as sensitivity analyses 
provided there are enough data points for a meaningful analysis. 
Assuming the true complete remission rates in the ITT study population are 30% and 50% for 
the placebo and selumetinib-containing arms, respectively, the study will have at least 80% 
power to demonstrate a statistically significant difference at the 5% (2-sided) significance 
level.  
All secondary endpoints will be analysed at the time of the primary analysis. Exploratory 
biomarker analysis may be analysed after the time of the primary analysis and reported 
separately to the CSR (apart from the somatic genetic data required for analysis of the second 
primary endpoint). 
All randomised patients will continue to be followed until the final study visit (3 years after 
their RAI treatment). At this time, data on clinical status, incidence of re-treatment and long-
term safety will be summarised. 
Reason for Amendment: 
AstraZeneca amended this section of the protocol to accommodate changes made to the 
section 12 as a result of moving the co-primary objective to secondary. 
 


Clinical Study Protocol Amendment 2 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 15 July 2013 
5(17) 
Section of protocol affected: 
3.2 
Rationale for study design, doses and control group 
Previous text: 
The primary efficacy endpoint will be assessed in patients with tumours carrying BRAF or 
NRAS mutations, as these are known to constitutively activate the MEK signalling pathway. 
Treatment with a MEK inhibitor may thus be hypothesised to deliver a greater treatment effect 
in these patients. However, the pathway can be activated in many ways such that these 
patients are not likely to be the only population to benefit. Incorporation of a genetically 
predefined study population enables this hypothesis to be examined (mutation analysis of 
samples to identify the genetically predefined study population will be performed post-
randomisation, and prior to data base lock for the primary endpoint data analysis). 
Revised text: 
A secondary efficacy endpoint will be assessed in patients with tumours carrying BRAF or 
NRAS mutations, as these are known to constitutively activate the MEK signalling pathway. 
Treatment with a MEK inhibitor may thus be hypothesised to deliver a greater treatment effect 
in these patients. However, the pathway can be activated in many ways such that these 
patients are not likely to be the only population to benefit. Incorporation of a genetically 
predefined study population enables this hypothesis to be examined (mutation analysis of 
samples to identify the genetically predefined study population will be performed post-
randomisation, and prior to data base lock for the primary endpoint data analysis). 
Reason for Amendment: 
AstraZeneca amended this section due to changes in the study primary and secondary 
objectives.  
 
Section of protocol affected: 
4.1 
Inclusion criteria 
Previous text: 
14. 
Adequate organ function as defined by: 
(a) 
ANC  1.5x109/L (1500 per mm3) 
(b) 
Platelets  100 x 109/L (100,000 per mm3) 
Revised text: 
14. 
Adequate organ function as defined by: 


Clinical Study Protocol Amendment 2 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 15 July 2013 
6(17) 
(a) 
ANC  1.5 x 109/L (1500 per mm3) 
(b) 
Platelets  100 x 109/L (100,000 per mm3) 
Reason for Amendment: 
AstraZeneca corrected text formatting errors.  
 
Section of protocol affected: 
4.2 
Exclusion criteria 
Additional text: 
7. Receiving herbal supplements or medications known to be strong inhibitors or 
inducers of the CYP1A2, CYP2C19 and CYP3A4 enzymes unless such products can 
be safely discontinued at least 14 days before the first dose of study medication. 
Reason for Amendment:  
Exclusion criterion added at FDA request. 
 
Section of protocol affected: 
6.2 
Data collection at enrolment 
Additional text: 
13. Local derived BRAF and/or NRAS mutation status (where available) 
Reason for Amendment:  
Clarification to data collection plans by AstraZeneca.  
 
Section of protocol affected: 
6.5.7.2 Resting 12-lead ECG 
Previous text: 
During the treatment phase of the study, patients will have single 12-lead ECGs assessments 
at the following timepoints: 
x
1-2 hours after the first dose of study treatment on Day 1 


Clinical Study Protocol Amendment 2 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 15 July 2013 
7(17) 
x
1-2 hours after the first dose of study treatment on Day 29 or 30 
x
At the 30-day follow up visit following completion of study treatment   
x
Single ECGs must also be performed at the time of any ECHO/MUGA assessment, 
and on occurrence of any cardiorespiratory adverse event   
x
A single 12-lead ECG is also required at premature discontinuation of treatment 
Revised text: 
During the treatment phase of the study, patients will have single 12-lead ECGs assessments 
at the following timepoints: 
x
1-2 hours after the first dose of study treatment on Day 1 
x
1-2 hours after the morning dose of study treatment on Day 29 or 30 
x
At the 30-day follow up visit following completion of study treatment   
x
Single ECGs must also be performed at the time of any ECHO/MUGA assessment, 
and on occurrence of any cardiorespiratory adverse event   
x
A single 12-lead ECG is also required at premature discontinuation of treatment 
Reason for Amendment: 
Clarification by AstraZeneca. 
 
Section of protocol affected: 
6.10.1 BRAF and NRAS patient population 
Previous text: 
Archival tumour sample from every patient will be analysed for BRAF and NRAS mutational 
status centrally using standardised methodology. Full analytical methodology details will be 
provided in the CSR. 
The genetic analysis of archival tumour samples to identify the BRAF and NRAS patient 
population will be performed retrospectively in the study (after randomisation but prior to the 
primary endpoint data analysis). 
BRAF/NRAS positive = mutations in BRAF/NRAS have been detected 
BRAF/NRAS negative = no mutation in BRAF/NRAS has been detected   


Clinical Study Protocol Amendment 2 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 15 July 2013 
8(17) 
BRAF/NRAS unknown = mutation status in BRAF/NRAS cannot be confirmed 
Revised text: 
Archival tumour sample from each patient will be analysed for BRAF and NRAS mutational 
status centrally using standardised methodology. Analysis may include, but is not limited to, 
BRAF V600E and NRAS Q61R, Q61K, Q61L. Full analytical methodology details will be 
provided in the CSR. 
The genetic analysis of archival tumour samples to identify the BRAF and NRAS patient 
population will be performed retrospectively in the study (after randomisation but prior to the 
primary endpoint data analysis). 
BRAF/NRAS positive = mutations in BRAF/NRAS have been detected 
BRAF/NRAS not detected = no mutation in BRAF/NRAS has been detected   
BRAF/NRAS unknown = mutation status in BRAF/NRAS cannot be confirmed 
Reason for Amendment:  
FDA comments. 
Clarification of terminology by AstraZeneca. 
 
Section of protocol affected: 
7.1 
Volume of blood 
Table 9     Volume of blood to be drawn from each patient  
Previous text: 
Table 9 
Volume of blood to be drawn from each patient  
Assessment 
Maximum 
sample 
volume a 
(mL) 
Typical 
number of 
samples (over 
18+ months) 
Total volume 
(mL) 
Safety 
Clinical chemistry (local analysis) 
5 
5 
25 
 
Haematology (local analysis) 
3 
7 
21 
Efficacy 
Tg, TSH, TgAb (central analysis) 
10 
4 
40 
PK 
2 
8 
16 
Genetics at randomisation (optional) 
10 
1 
10 


Clinical Study Protocol Amendment 2 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 15 July 2013 
9(17) 
Table 9 
Volume of blood to be drawn from each patient  
Assessment 
Maximum 
sample 
volume a 
(mL) 
Typical 
number of 
samples (over 
18+ months) 
Total volume 
(mL) 
Safety 
Clinical chemistry (local analysis) 
5 
5 
25 
 
Haematology (local analysis) 
3 
7 
21 
Efficacy 
Tg, TSH, TgAb (central analysis) 
10 
4 
40 
PK 
2 
8 
16 
Exploratory biomarkers at randomisation, serum  
10 
1 
10 
Exploratory biomarkers at randomisation, plasma  
10 
1 
10 
Exploratory biomarkers on progression, serum  
10 
1 
10 
Exploratory biomarkers on progression, plasma  
10 
1 
10 
Total 
 
 
152  
a All volumes presented are maximums. The actual volume requirements will be detailed in the Laboratory 
Manual. 
 
Revised text: 
Table 9 
Volume of blood to be drawn from each patient  
Assessment 
Maximum 
sample 
volume a 
(mL) 
Typical 
number of 
samples (over 
18+ months) 
Total volume 
(mL) 
Safety 
Clinical chemistry (local analysis) 
5 
5 
25 
 
Haematology (local analysis) 
3 
7 
21 
Efficacy 
Tg, TSH, TgAb (central analysis) 
10 
4b 
40 
PK 
2 
8 
16 
Genetics at randomisation (optional) 
10 
1 
10 
Exploratory biomarkers at randomisation, serum  
10 
1 
10 
Exploratory biomarkers at randomisation, plasma  
10 
1 
10 
Exploratory biomarkers on progression, serum  
10 
1 
10 
Exploratory biomarkers on progression, plasma  
10 
1 
10 
Total 
 
 
152 b 


Clinical Study Protocol Amendment 2 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 15 July 2013 
10(17) 
a All volumes presented are maximums. The actual volume requirements will be detailed in the Laboratory 
Manual. 
b For efficacy samples up to 2 repeat samples may be required, this would result in 10-20 mL additional 
blood and bring the maximum total to 172 mL. 
 
Reason for Amendment:  
Clarification to blood sampling plan and total blood volumes by AstraZeneca. 
 
Section of protocol affected: 
11.5.1 Analysis of NRAS and BRAF 
Previous text: 
Tumour samples will be collected as outlined in the study plan and assessed for BRAF and 
NRAS biomarkers to identify patients for this primary patient population. 
Revised text: 
Tumour samples will be collected as outlined in the study plan and assessed for BRAF and 
NRAS mutational status (as detailed in section 6.10.1) to identify patients for this patient 
population. 
Reason for Amendment:  
Clarifications by AstraZeneca. 
 
Section of protocol affected: 
12.1.2 BRAF/NRAS mutation positive analysis set 
Previous text: 
For the analysis of the BRAF and NRAS mutation positive population (primary objective), 
only those patients from the ITT population with genetic samples that are positive for BRAF 
or NRAS will be included. 
Revised text: 
For the analysis of the BRAF and NRAS mutation positive population (secondary objective), 
only those patients from the ITT population with genetic samples that are positive for BRAF 
or NRAS will be included. 


Clinical Study Protocol Amendment 2 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 15 July 2013 
11(17) 
Reason for Amendment: 
AstraZeneca amended this section due to changes in the study primary and secondary 
objectives.  
 
Section of protocol affected: 
12.1.4  Safety analysis set 
Previous text: 
The safety analysis set will consist of all patients who received at least one dose of 
randomised treatment and for whom post dose data are available. Safety data will not be 
formally analysed but summarised using the safety analysis set, according to the treatment 
combination received, ie, erroneously treated patients (eg, those randomised to treatment A 
but actually given treatment B) will be summarised according to the treatment they actually 
received. 
Revised text: 
The safety analysis set will consist of all patients who received at least one dose of 
randomised treatment. Safety data will not be formally analysed but summarised using the 
safety analysis set, according to the treatment combination received, ie, erroneously treated 
patients (eg, those randomised to treatment A but actually given treatment B) will be 
summarised according to the treatment they actually received. 
Reason for Amendment: 
Clarification by AstraZeneca. 
 
Section of protocol affected: 
12.2 
Methods of statistical analyses 
Previous text: 
A comprehensive SAP will be prepared prior to start of recruitment (first subject in).  
Since there are two correlated primary comparisons of interest (selumetinib vs. placebo in the 
overall population and selumetinib vs. placebo in the mutation-positive population), the 
Dunnett and Tamhane step-up procedure will be used to control the type I error rate (Dunnett 
and Tamhane 1992, Fernandes & Stone 2011). This procedure is an adaptation of the 
Hochberg approach, which accounts for the correlation between the primary endpoint 
comparisons. The correlation between the primary endpoint comparisons will be calculated as 
¥w, where w is the proportion of the overall population who are in the mutation positive sub-
group. The associated significance level for declaring statistical significance in the mutation 


Clinical Study Protocol Amendment 2 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 15 July 2013 
12(17) 
positive sub-group adjusting for this correlation to maintain an overall 5% type I error rate 
whilst assigning 4% to the overall population will then be derived. For example, assuming that 
55% of the overall population are in the mutation-positive sub-group, the correlation is 0.74. 
Using Dunnett and Tamhane step-up procedure, significance would therefore be declared if 
both the overall and mutation positive populations are significant at the 5% two-sided level, or 
if either the overall population is significant at the 4% level or the mutation-positive 
population is significant at the 1.625% level. 
12.2.1 Complete remission rate at 18 months post-RAI treatment 
The endpoint of complete remission rate will be compared between selumetinib in 
combination with RAI, and placebo in combination with RAI in the overall population using a 
logistic regression model with covariates histology status (papillary, follicular, poorly 
differentiated), mutation status (BRAF/NRAS positive, BRAF/NRAS negative) and age, 
provided there are enough data points for a meaningful analysis.  
The primary endpoint of complete remission rate will be compared between selumetinib in 
combination with RAI vs. placebo in combination with RAI in the mutation positive 
population using a logistic regression model with covariates histology status (papillary, 
follicular, poorly differentiated) and age, provided there are enough data points for a 
meaningful analysis. 
For each covariate, if the status is missing or unknown, patients will be assigned to the status 
that the majority of patients are known to have, e.g. if 55% of patients with known mutation 
status are BRAF/NRAS positive and 45% are BRAF/NRAS negative, a patient with missing 
mutation status will be assigned BRAF/NRAS positive. If a value for the continuous covariate 
age is missing, the mean will be imputed. 
The results of the analysis will be presented in terms of an odds ratio together with its 
associated 95% profile likelihood confidence interval and 2-sided p-value. The p-value will be 
based on twice the change in log-likelihood resulting from the addition of a treatment factor to 
a model that contains the covariates defined above. The complete remission rate will be 
estimated for each treatment arm. 
Sensitivity analyses 
The primary endpoint analysis will be repeated using the treatment-compliant population. 
A sensitivity analysis will be performed in which patients that were identified as being in 
complete remission outside of the specified time windows will be included in the logistic 
regression analysis and classed as being in complete remission to ensure there is no evaluation 
time bias between arms.  
Elevated TSH can be caused by poor compliance and can mean a patient is less likely to 
achieve remission. A sensitivity analysis will be performed in which patients with high TSH 


Clinical Study Protocol Amendment 2 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 15 July 2013 
13(17) 
are excluded from the logistic regression. A high TSH is defined as a value >10 mIU/L 
recorded at any point by standardised central laboratory analysis. 
The extent to which the treatment effect is consistent across the subgroups histology status, 
mutation status, gender, race and age will be assessed for the overall primary population and 
across the subgroups histology status, gender, race and age for the mutation positive primary 
population. The presence of a quantitative interaction will be assessed by means of an overall 
global interaction test. This will be performed by comparing the fit (likelihood ratio test) of a 
model including all covariate-by-randomised treatment interaction terms, treatment and 
covariate terms with a model that excludes the interaction terms. If the global interaction test 
is found to be statistically significant at the 10% significance level, an attempt to determine 
the cause and type of interaction will be made. Stepwise backward selection will be performed 
on the saturated model, whereby (using a 10% level throughout) the least significant 
interaction terms are removed one-by-one and any newly significant interactions re-included 
until a final model is reached where all included interactions are significant and all excluded 
interactions are non-significant.  Throughout this process all main effects will be included in 
the model regardless of whether the corresponding interaction term is still present.  This 
approach will identify the factors that independently alter the treatment effect and prevent 
identification of multiple correlated interactions. 
For quantitative interactions identified, the presence of any qualitative interactions will be 
assessed using the approach of Gail and Simon (Gail & Simon 1985). For categorical 
covariates the test statistics, based on the appropriate degrees-of-freedom, can be taken 
directly from the paper. For the continuous covariate, the approach will be adapted as follows:  
Identify the cut-point (-E1/E3) of the covariate where the odds ratio for the treatment effect is 
1, where ȕ1 is the treatment parameter estimate and ȕ3 is the treatment-by-covariate parameter 
estimate. Re-analyse the data separately for the values of the covariate above and below the 
cut-point and use the separate chi-square values in the Simon and Gail test. 
Subgroup data (histology status, mutation status, gender, race and age) will be summarised by 
a forest plot where the odds ratio is plotted on the log scale. For this, age will be categorised 
as 45 or >45 years. The treatment effect and confidence intervals for each level of the 
subgroup will be obtained from a single model that contains a treatment, factor and treatment-
by-factor interaction term.  
12.2.2 Clinical remission rate at 18 months post-RAI treatment 
The secondary endpoint of clinical remission rate will be analysed (for both study 
populations) as described in Section 12.2.1. 
Revised text: 
A comprehensive SAP will be prepared prior to start of recruitment (first subject in).  


Clinical Study Protocol Amendment 2 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 15 July 2013 
14(17) 
Since there is only one primary endpoint/comparison of interest (complete remission rate 
at 18 months for selumetinib vs. placebo in the ITT population) the primary endpoint 
will be considered statistically significant if the two-sided p-value is less than 0.05.  
12.2.1 Complete remission rate at 18 months post-RAI treatment 
The primary endpoint of complete remission rate at 18 months will be compared between 
selumetinib in combination with RAI, and placebo in combination with RAI in the ITT 
population using a logistic regression model including treatment as the only covariate. 
Results will be presented in terms of the odds ratio, 95% confidence interval and 
associated p-value. A sensitivity analysis will be performed using a logistic regression 
model including treatment and adjusted for the covariates histology status (papillary, 
follicular, poorly differentiated), mutation status (BRAF/NRAS positive, BRAF/NRAS not 
detected) and age, provided there are enough data points for a meaningful analysis.  
A secondary analysis of complete remission rate will be performed to compare selumetinib 
in combination with RAI vs. placebo in combination with RAI in the BRAF/NRAS mutation 
positive population using a logistic regression model including treatment as the only 
covariate.  A sensitivity analysis will be performed using a logistic regression model 
adjusted for the covariates histology status (papillary, follicular, poorly differentiated) and 
age, provided there are enough data points for a meaningful analysis. 
For the sensitivity analyses using each covariate adjusted logistic regression models, the 
following missing data approach for each covariate will be adopted: 
x
Missing age; impute the mean of observed ages 
x
Missing histology status; add an additional ‘unknown’ category to make 4 
categories (papillary, follicular, poorly differentiated, and unknown) 
x
Missing mutation status; add an additional ‘unknown’ category to make 3 
categories (BRAF/NRAS positive, BRAF/NRAS not detected and unknown) 
The results of the analyses, in terms of treatment effects, will be presented as odds ratios 
together with their associated 95% profile likelihood confidence intervals and 2-sided p-
values. The p-value will be based on twice the change in log-likelihood resulting from the 
addition of a treatment factor to a model that contains the covariates defined above. The 
complete remission rate and 95% confidence interval will be estimated for each treatment 
arm. 
Sensitivity analyses for the primary endpoint 
The primary endpoint analysis, a logistic regression model including treatment as the only 
covariate for complete remission rate at 18 months, will be repeated:  
x
using the treatment-compliant population. 


Clinical Study Protocol Amendment 2 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 15 July 2013 
15(17) 
x
to allow patients that were identified as being in complete remission outside of the 
specified time windows to be classed as being in complete remission, in order to 
investigate time bias between arms.  
x
excluding patients with high TSH. Elevated TSH can be caused by poor 
compliance and can mean a patient is less likely to achieve remission, therefore this 
sensitivity analysis excludes patients with high TSH, which is defined as a value 
>10 mIU/L recorded at any point by standardised central laboratory analysis. 
Treatment by covariate interactions 
The extent to which the treatment effect is consistent across the subgroups histology status, 
mutation status (ITT population only), gender, race and age will be assessed in the ITT 
population and in the BRAF/NRAS mutation positive population. The presence of a 
quantitative interaction will be assessed by means of an overall global interaction test. This 
will be performed by comparing the fit (likelihood ratio test) of a model including all 
covariate-by-randomised treatment interaction terms, treatment and covariate terms with a 
model that excludes the interaction terms. If the global interaction test is found to be 
statistically significant at the 10% significance level, an attempt to determine the cause and 
type of interaction will be made. Stepwise backward selection will be performed on the 
saturated model, whereby (using a 10% level throughout) the least significant interaction 
terms are removed one-by-one and any newly significant interactions re-included until a final 
model is reached where all included interactions are significant and all excluded interactions 
are non-significant.  Throughout this process all main effects will be included in the model 
regardless of whether the corresponding interaction term is still present.  This approach will 
identify the factors that independently alter the treatment effect and prevent identification of 
multiple correlated interactions. 
For quantitative interactions identified, the presence of any qualitative interactions will be 
assessed using the approach of Gail and Simon (Gail & Simon 1985). For categorical 
covariates the test statistics, based on the appropriate degrees-of-freedom, can be taken 
directly from the paper. For the continuous covariate, the approach will be adapted as follows:  
Identify the cut-point (-ȕ1/ȕ3) of the covariate where the odds ratio for the treatment effect is 1, 
where ȕ1 is the treatment parameter estimate and ȕ3 is the treatment-by-covariate parameter 
estimate. Re-analyse the data separately for the values of the covariate above and below the 
cut-point and use the separate chi-square values in the Simon and Gail test. 
Subgroup data 
Subgroup data (histology status, BRAF or NRAS mutation status, gender, race and age) will 
be summarised by a forest plot where the odds ratio is plotted on the log scale. For this, age 
will be categorised as 45 or >45 years. The treatment effect and 95% confidence intervals 
for each level of the subgroup will be obtained from a single logistic regression model that 
contains a treatment, factor and treatment-by-factor interaction term.  
12.2.2 Clinical remission rate at 18 months post-RAI treatment 


Clinical Study Protocol Amendment 2 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 15 July 2013 
16(17) 
The secondary endpoint of clinical remission rate will be analysed as described in Section 
12.2.1, except for primary endpoint specific sensitivity analyses and treatment by 
covariate interaction testing. 
Reason for Amendment: 
FDA comments. Clarification of terminology from the FDA response document submitted by 
AstraZeneca on 27th June 2013.  
 
Section of protocol affected: 
12.3 
Determination of sample size 
Previous text: 
The sample size for this study was selected to be consistent with the research hypothesis as 
described in Section 1.2. 
The two primary objectives of the study are to compare the efficacy of selumetinib with RAI 
versus placebo with RAI, by assessment of the complete remission rate at 18 months post-RAI 
treatment in the overall study population, and in a sub-group of patients whose tumours have 
BRAF and NRAS mutations. Assuming the true complete remission rates in the overall study 
population are 30% and 50% for the placebo and selumentinib-containing arms, respectively, 
a total of 228 patients, randomised in a 2:1 ratio (152 and 76 patients in the selumentinib and 
placebo-containing arms, respectively) provides 80% power to show statistical significance, 
based on a two-sided 4% significance level. Assuming that the prevalence of the mutation-
positive sub-group described is 55%, and the true complete remission rates in the mutation-
positive sub-group are 30% and 62% for the placebo and selumentinib-containing arms, 
respectively, the expected numbers of 84 mutation-positive patients in the selumentinib arm 
and 42 mutation-positive patients in the placebo arm at the time of the analysis, provides 80% 
power to show statistical significance, based on a two-sided 1% significance level. 
Revised text: 
The sample size for this study was selected to be consistent with the research hypothesis as 
described in Section 1.2. 
The primary objective of the study is to compare the efficacy of selumetinib with RAI versus 
placebo with RAI, by assessment of the complete remission rate at 18 months post-RAI 
treatment in the ITT study population. Assuming the true complete remission rates in the 
overall study population are 30% and 50% for the placebo and selumentinib-containing arms, 
respectively, a total of 228 patients, randomised in a 2:1 ratio (152 and 76 patients in the 
selumentinib and placebo-containing arms, respectively) provides at least 80% power to show 
statistical significance, based on a two-sided 5% significance level. 


Clinical Study Protocol Amendment 2 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 15 July 2013 
17(17) 
Reason for Amendment:  
FDA comments.  
 
Section of protocol affected: 
14. 
List of references 
Removed text: 
Dunnett and Tamhane 1992 
Dunnett CW, Tamhane AC. A Step-Up Multiple Test Procedure. J Am Stat Assoc 1992; 
87(417):162-170.  
Fernandes & Stone 2011 
Fernandes N & Stone A. Multiplicity adjustments in trials with two correlated comparisons of 
interest. Stat Methods Med Res. 2011;20(6):579-594. 
Reason for Amendment: 
AstraZeneca removed two publications related to statistics (Dunnett and Tamhane 1992, 
Fernandes & Stone 2011) due to changes in statistical methods (the Dunnett and Tamhane 
step-up procedure).  
 Persons who initiated the Amendment: 
AstraZeneca at FDA request.  


 
 
Clinical Study Protocol Amendment No 2 Appendix 
A 
 
Drug Substance 
Selumetinib (AZD6244) 
 
Study Code 
D1532C00065 
 
Edition Number 
1 
 
Date 
15 July 2013 
 
Protocol Dated 
24 January 2013 
 
 
 
 
 
 
 
 
 
Appendix A 
Signatures 
 


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Clinical Study Protocol Amendment No 2 Appendix A 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Edition Number 1 
Date 15 July 2013 
3(5) 
ASTRAZENECA SIGNATURE(S) 
 
 
   
A Randomised, Double Blind Study to Compare the Complete Remission 
Rate Following a 5-Week Course of Selumetinib or Placebo and Single Dose
Adjuvant Radioactive Iodine Therapy in Patients with Differentiated 
Thyroid Cancer 
 
This Clinical Study Protocol and all Amendments to the CSP have been subjected to an 
internal AstraZeneca peer review.  
 
I agree to the terms of this study protocol/amendment. 
 
 
 
AstraZeneca Research and Development
site representative 
 
 
 
This document contains confidential information, which should not be copied, referred to, 
released or published without written approval from AstraZeneca.  Investigators are cautioned 
that the information in this protocol may be subject to change and revision. 
 
ONC.000−602−842.3.0 (Version Created 16 Jul 2013 10:28:42)
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Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
 
Clinical Study Protocol Amendment  
 
Amendment Number 
3 
 
Drug Substance 
Selumetinib (AZD6244) 
 
Study Code 
D1532C00065 
 
Date 
01 July 2014 
 
Protocol Dated 
24 January 2013 
 
 
 
 
 
 
 
 
 
 
A Randomised, Double Blind Study to Compare the Complete Remission 
Rate Following a 5-Week Course of Selumetinib or Placebo and Single Dose 
Adjuvant Radioactive Iodine Therapy in Patients with Differentiated 
Thyroid Cancer 
 
 
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
Sponsor: 
AstraZeneca AB, 151 85 Södertälje, Sweden   
Centres affected by the Amendment: 
This protocol amendment affects all the centres participating in this study. 
The protocol for the study is to be amended as follows:  
 
Section of protocol affected: 
1.1.5.4      The pharmacokinetics of Selumetinib in subjects of Asian ethnicity 
Previous text: 
Blank 
Revised text: 
Plasma exposure of Selumetinib (Cmax and AUC) is higher, at a population level, in subjects 
of Asian ethnicity by approximately 1.5- to 2-fold in non-Japanese Asians and Japanese 
subjects, compared with Western subjects.  However, the pharmacokinetics of Selumetinib 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
2(32) 
show considerable variation and there is overlap in the range of exposure experienced by 
Asian and Western subjects (some individual Asian subjects have similar plasma levels to 
those in Western subjects).  The higher average plasma exposure was not associated with a 
change in the tolerability profile of single dose Selumetinib.   
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 
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. 
Reason for Amendment:  
Availability of preliminary study D1532C00086 data suggesting that subjects of Asian descent 
may experience a higher exposure of Selumetinib than the majority of subjects of non Asian 
descent receiving an equivalent dose of Selumetinib. 
 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
3(32) 
Section of protocol affected: 
3.1.1. Treatment Plan 
Previous text: 
2.   
It is essential that patients remain on study treatment continuously for a minimum of 7       
consecutive days prior to their planned RAI therapy, on the day of RAI therapy, and 
for 5 consecutive days afterwards.  If necessary, RAI therapy may be rescheduled at 
the discretion of the Investigator until the patient has been on study treatment for a 
minimum of 7 consecutive days beforehand.   
3.   
Study treatment with selumetinib or placebo will typically last for 36 days, but must be 
for no longer than 43 days (this allows the planned RAI to be postponed by up to 1 
week if absolutely necessary).  
7.  
Twice daily dosing of selumetinib/placebo will continue for 5 days following RAI 
therapy (Day 36 will typically be the last day of study treatment, but this can be 
extended to day 43 if necessary) 
Revised text: 
2.   
Patients should remain on study treatment continuously for a minimum of 7 
consecutive days prior to their planned RAI therapy, on the day of RAI therapy, and 
for 5 consecutive days afterwards.  If necessary, RAI therapy may be rescheduled at 
the discretion of the Investigator to allow the patient to receive study treatment for a 
minimum of 7 consecutive days beforehand. 
3.   
Study treatment with selumetinib or placebo will typically last for 36 days, but must be 
for no longer than 43 days. The planned RAI can be postponed by up to 1 week if 
absolutely necessary. 
7.   
Twice daily dosing of selumetinib/placebo should continue for 5 days following RAI 
therapy 
8.   
If a patient suspends study drug (selumetinib or placebo) treatment for more than 14 
days they are no longer eligible to re-start the treatment but will be followed according 
to the study plan. 
 
Reason for Amendment:  
Amended to clarify visit window for RAI treatment dose administration and provide clear 
instruction on allowed IP interruption. 
 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
4(32) 
 
Section of protocol affected: 
Table 3 Study Plan 
Previous text 
 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
5(32) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Visit Description 
Screening 
Randomi
sation 
On -
treatment 
safety 
visit 
Thyrogen 
RAI 
therapy 
Last day 
of 
treatment 
30 days 
post 
treatment 
4 Month 
safety 
follow up 
9 
Month 
FU 
Primary 
endpoint 
assessmentsa 
27 
Month 
safety 
follow up 
3 Year 
FU 
Protocol 
Section 
Timing 
Day  
-28 to –1 
Day 1 
Day 14 
Days  
29 & 30 
Day 31 
 Day 36 
Week 10 
4 months 
post visit 
5 
9 
months 
post 
visit 5 
18 months 
post visit 5 
27 
months 
post visit 
5 
3 years 
post 
visit 5 
 
Visit Window 
N/A 
N/A 
±1wk 
N/A 
N/A 
N/A 
± 2 days 
± 2 
weeks 
± 3 
months 
Refer to 
Table 4 
± 2 
months 
± 1 
month 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
X 
X 
(Day 29 
or 30) 
 
 
X 
 
 
 
 
 
6.5.6 
Additional screening 
procedures 
X 
 
 
 
 
 
 
 
 
 
 
 
6.2 
Provision of archival 
tumourb 
 
X 
 
 
 
 
 
 
 
 
 
 
6.10.1.
1 
Plasma/serum sample for 
exploratory analysisb 
 
X (pre-
dose) 
 
 
 
 
 
 
 
 
 
 
6.10.2 
Pregnancy test 
X 
 
 
 
X 
 
 
 
 
Xa 
 
 
6.5.9.1 
Optional genetic consent & 
sample (whole blood) 
 
X (pre-
dose) 
 
 
 
 
 
 
 
 
 
 
6.9 
Adverse eventsc 
X 
 
 
 
 
 
 
 
 
 
 
 
6.5.3 
Concomitant medications 
X 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Telephone follow up for 
safetyd 
 
 
 
 
 
 
 
X 
 
 
X 
 
6.5.3 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
6(32) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Visit Description 
Screening 
Randomi
sation 
On -
treatment 
safety 
visit 
Thyrogen 
RAI 
therapy 
Last day 
of 
treatment 
30 days 
post 
treatment 
4 Month 
safety 
follow up 
9 
Month 
FU 
Primary 
endpoint 
assessmentsa 
27 
Month 
safety 
follow up 
3 Year 
FU 
Protocol 
Section 
Timing 
Day  
-28 to –1 
Day 1 
Day 14 
Days  
29 & 30 
Day 31 
 Day 36 
Week 10 
4 months 
post visit 
5 
9 
months 
post 
visit 5 
18 months 
post visit 5 
27 
months 
post visit 
5 
3 years 
post 
visit 5 
 
Visit Window 
N/A 
N/A 
±1wk 
N/A 
N/A 
N/A 
± 2 days 
± 2 
weeks 
± 3 
months 
Refer to 
Table 4 
± 2 
months 
± 1 
month 
 
Vital signs (including height 
at screening), weight 
X 
X (pre-
dose) 
X 
X 
(Day 29 
or 30) 
 
 
X 
 
 
 
 
 
6.5.8 
Clinical chemistry 
X 
X (pre-
dose) 
X 
X 
(Day 29 
or 30) 
 
 
X 
 
 
 
 
 
6.5.5 
Haematology 
X 
X (pre-
dose) 
X 
X 
(Day 29 
or 30) 
 
 
X 
 
 
X 
 
X 
6.5.5 
Urinalysis 
X 
 
X 
 
 
 
X 
 
 
 
 
 
6.5.5 
ECGe 
X 
X 
 
Xe (Day 
29 or 30) 
 
 
X 
 
 
 
 
 
6.5.7.2 
ECHO/MUGAf 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
6.5.7.1 
Ophthalmologic 
examinationf 
X 
 
 
 
 
 
X 
 
 
 
 
 
6.5.9.2 
Selumetinib/placebo dosingg 
twice daily 
 
 
 
 
 
 
 
 
 
 
 
 
5.5.2 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
7(32) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Visit Description 
Screening 
Randomi
sation 
On -
treatment 
safety 
visit 
Thyrogen 
RAI 
therapy 
Last day 
of 
treatment 
30 days 
post 
treatment 
4 Month 
safety 
follow up 
9 
Month 
FU 
Primary 
endpoint 
assessmentsa 
27 
Month 
safety 
follow up 
3 Year 
FU 
Protocol 
Section 
Timing 
Day  
-28 to –1 
Day 1 
Day 14 
Days  
29 & 30 
Day 31 
 Day 36 
Week 10 
4 months 
post visit 
5 
9 
months 
post 
visit 5 
18 months 
post visit 5 
27 
months 
post visit 
5 
3 years 
post 
visit 5 
 
Visit Window 
N/A 
N/A 
±1wk 
N/A 
N/A 
N/A 
± 2 days 
± 2 
weeks 
± 3 
months 
Refer to 
Table 4 
± 2 
months 
± 1 
month 
 
 
PK blood samplesh 
 
X 
 
Xh (Day 
29 or 30) 
 
 
 
 
 
 
 
 
6.7 
Low iodine dieti 
 
 
 
X 
X 
 
 
 
 
Xa 
 
 
5.1.1 
Thyrogen injection 
 
 
 
Xx2 
(Day 29 
and 30) 
 
 
 
 
 
Xx2a 
 
 
5.5.4.1 
131I (RAI) treatment 
single 100 mCi dose 
 
 
 
 
X 
 
 
 
 
 
 
 
5.5.4.2 
131I 5 diagnostic dose for 
WBS 
single 5 mCi dose 
 
 
 
 
 
 
 
 
 
Xa 
 
 
5.5.4.2 
131I nuclear medicine WBS 
scan 
 
 
 
 
 
Xj 
 
 
 
Xa 
 
 
6.4.4.2 
Re-treatment assessmentk 
 
 
 
 
 
 
 
 
X 
X 
 
X 
5.9 
Blood sample for TSH 
 
 
 
 
 
 
 
 
X 
X 
 
 
6.4.3.3 
Blood sample for 
suppressed Tg 
 
 
 
 
 
 
 
 
Xn 
X 
 
 
6.4.3.1 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
8(32) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Visit Description 
Screening 
Randomi
sation 
On -
treatment 
safety 
visit 
Thyrogen 
RAI 
therapy 
Last day 
of 
treatment 
30 days 
post 
treatment 
4 Month 
safety 
follow up 
9 
Month 
FU 
Primary 
endpoint 
assessmentsa 
27 
Month 
safety 
follow up 
3 Year 
FU 
Protocol 
Section 
Timing 
Day  
-28 to –1 
Day 1 
Day 14 
Days  
29 & 30 
Day 31 
 Day 36 
Week 10 
4 months 
post visit 
5 
9 
months 
post 
visit 5 
18 months 
post visit 5 
27 
months 
post visit 
5 
3 years 
post 
visit 5 
 
Visit Window 
N/A 
N/A 
±1wk 
N/A 
N/A 
N/A 
± 2 days 
± 2 
weeks 
± 3 
months 
Refer to 
Table 4 
± 2 
months 
± 1 
month 
 
Blood sample for TgAb 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
6.4.3.4 
Blood sample for rhTSH-
stimulated Tg 
 
 
 
 
 
 
 
 
 
Xa 
 
 
6.4.3.2 
Neck ultrasound 
Xl 
 
 
 
 
 
 
 
X 
X 
 
 
6.4.4.1 
Neck MRI 
Xl 
 
 
 
 
 
 
 
 
Xa 
 
 
6.4.4.3 
Chest CT without contrast 
Xl 
 
 
 
 
 
 
 
 
Xa 
 
 
6.4.4.4 
Final follow-up assessment 
of clinical status 
 
 
 
 
 
 
 
 
 
 
 
X 
6.4.8 
Biopsy/FNA for disease 
confirmation 
 
 
 
 
 
 
 
 
Xm 
Xm 
 
 
6.4.4.5 
Tumour biopsy on 
progression (optional) 
Optional sample on disease progression (for example, if the patient is re-treated for persistent or recurrent thyroid cancer, or has further surgery). 
Note that both a plasma and serum sample for exploratory analysis should also be taken on disease progression. 
6.10.3 
6.10.2 
 
Revised Text: 
 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
9(32) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Visit Description 
Screening 
Randomi
sation 
On -
treatment 
safety 
visit 
Thyrogen 
RAI 
therapy 
Last day 
of 
treatment 
30 days 
post 
treatment 
4 Month 
safety 
follow up 
9 
Month 
FU 
Primary 
endpoint 
assessmentsa 
27 
Month 
safety 
follow up 
3 Year 
FU 
Protocol 
Section 
Timing 
Day  
-28 to –1 
Day 1 
Day 14 
Days  
29 & 30 
Day 31 
 Day 36 
Week 10 
4 months 
post RAI 
(visit 5) 
9 
months 
post 
RAI 
(visit 5) 
18 months 
post RAI 
(visit 5) 
27 
months 
post RAI 
(visit 5) 
3 years 
post 
RAI 
(visit 5) 
 
Visit Window 
N/A 
N/A 
±1wk 
+1wk 
+1wk 
+1wk 
± 2 days 
± 2 
weeks 
± 3 
months 
Refer to 
Table 4 
± 2 
months 
± 1 
month 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
X 
X 
(Day 29 
or 30) 
 
 
X 
 
 
 
 
 
6.5.6 
Additional screening 
procedures 
X 
 
 
 
 
 
 
 
 
 
 
 
6.2 
Provision of archival 
tumourb 
 
X 
 
 
 
 
 
 
 
 
 
 
6.10.1.
1 
Plasma/serum sample for 
exploratory analysisb 
 
X (pre-
dose) 
 
 
 
 
 
 
 
 
 
 
6.10.2 
Pregnancy test 
X 
 
 
 
X 
 
 
 
 
Xa 
 
 
6.5.9.1 
Optional genetic consent & 
sample (whole blood) 
 
X (pre-
dose) 
 
 
 
 
 
 
 
 
 
 
6.9 
Adverse eventsc 
X 
 
 
 
 
 
 
 
 
 
 
 
6.5.3 
Concomitant medications 
X 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Telephone follow up for 
safetyd 
 
 
 
 
 
 
 
X 
 
 
X 
 
6.5.3 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
10(32) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Visit Description 
Screening 
Randomi
sation 
On -
treatment 
safety 
visit 
Thyrogen 
RAI 
therapy 
Last day 
of 
treatment 
30 days 
post 
treatment 
4 Month 
safety 
follow up 
9 
Month 
FU 
Primary 
endpoint 
assessmentsa 
27 
Month 
safety 
follow up 
3 Year 
FU 
Protocol 
Section 
Timing 
Day  
-28 to –1 
Day 1 
Day 14 
Days  
29 & 30 
Day 31 
 Day 36 
Week 10 
4 months 
post RAI 
(visit 5) 
9 
months 
post 
RAI 
(visit 5) 
18 months 
post RAI 
(visit 5) 
27 
months 
post RAI 
(visit 5) 
3 years 
post 
RAI 
(visit 5) 
 
Visit Window 
N/A 
N/A 
±1wk 
+1wk 
+1wk 
+1wk 
± 2 days 
± 2 
weeks 
± 3 
months 
Refer to 
Table 4 
± 2 
months 
± 1 
month 
 
Vital signs (including height 
at screening), weight 
X 
X (pre-
dose) 
X 
X 
(Day 29 
or 30) 
 
 
X 
 
 
 
 
 
6.5.8 
Clinical chemistry 
X 
X (pre-
dose) 
X 
X 
(Day 29 
or 30) 
 
 
X 
 
 
 
 
 
6.5.5 
Haematology 
X 
X (pre-
dose) 
X 
X 
(Day 29 
or 30) 
 
 
X 
 
 
X 
 
X 
6.5.5 
 
Urinalysis 
X 
 
X 
 
 
 
X 
 
 
 
 
 
6.5.5 
ECGe 
X 
X 
 
Xe (Day 
29 or 30) 
 
 
X 
 
 
 
 
 
6.5.7.2 
ECHO/MUGAf 
X 
 
 
 
 
 
X 
 
 
 
 
 
6.5.7.1 
Ophthalmologic 
examinationf 
X 
 
 
 
 
 
X 
 
 
 
 
 
6.5.9.2 
Selumetinib/placebo dosingg 
twice daily 
 
 
 
 
 
 
 
 
 
 
 
 
5.5.2 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
11(32) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Visit Description 
Screening 
Randomi
sation 
On -
treatment 
safety 
visit 
Thyrogen 
RAI 
therapy 
Last day 
of 
treatment 
30 days 
post 
treatment 
4 Month 
safety 
follow up 
9 
Month 
FU 
Primary 
endpoint 
assessmentsa 
27 
Month 
safety 
follow up 
3 Year 
FU 
Protocol 
Section 
Timing 
Day  
-28 to –1 
Day 1 
Day 14 
Days  
29 & 30 
Day 31 
 Day 36 
Week 10 
4 months 
post RAI 
(visit 5) 
9 
months 
post 
RAI 
(visit 5) 
18 months 
post RAI 
(visit 5) 
27 
months 
post RAI 
(visit 5) 
3 years 
post 
RAI 
(visit 5) 
 
Visit Window 
N/A 
N/A 
±1wk 
+1wk 
+1wk 
+1wk 
± 2 days 
± 2 
weeks 
± 3 
months 
Refer to 
Table 4 
± 2 
months 
± 1 
month 
 
PK blood samplesh 
 
X 
 
Xh (Day 
29 or 30) 
 
 
 
 
 
 
 
 
6.7 
Low iodine dieti 
 
 
 
X 
X 
 
 
 
 
Xa 
 
 
5.1.1 
Thyrogen injection 
 
 
 
Xx2 
(Day 29 
and 30) 
 
 
 
 
 
Xx2a 
 
 
5.5.4.1 
131I (RAI) treatment 
single 100 mCi dose 
 
 
 
 
X 
 
 
 
 
 
 
 
5.5.4.2 
131I 5 diagnostic dose for 
WBS 
single 5 mCi dose 
 
 
 
 
 
 
 
 
 
Xa 
 
 
5.5.4.2 
131I nuclear medicine WBS 
scan 
 
 
 
 
 
Xj 
 
 
 
Xa 
 
 
6.4.4.2 
Re-treatment assessmentk 
 
 
 
 
 
 
 
 
X 
X 
 
X 
5.9 
Blood sample for TSH 
 
 
 
 
 
 
 
 
X 
X 
 
 
6.4.3.3 
Blood sample for 
suppressed Tg 
 
 
 
 
 
 
 
 
Xn 
X 
 
 
6.4.3.1 
Blood sample for TgAb 
X 
 
 
 
 
 
 
 
X 
X 
 
 
6.4.3.4 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
12(32) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Visit Description 
Screening 
Randomi
sation 
On -
treatment 
safety 
visit 
Thyrogen 
RAI 
therapy 
Last day 
of 
treatment 
30 days 
post 
treatment 
4 Month 
safety 
follow up 
9 
Month 
FU 
Primary 
endpoint 
assessmentsa 
27 
Month 
safety 
follow up 
3 Year 
FU 
Protocol 
Section 
Timing 
Day  
-28 to –1 
Day 1 
Day 14 
Days  
29 & 30 
Day 31 
 Day 36 
Week 10 
4 months 
post RAI 
(visit 5) 
9 
months 
post 
RAI 
(visit 5) 
18 months 
post RAI 
(visit 5) 
27 
months 
post RAI 
(visit 5) 
3 years 
post 
RAI 
(visit 5) 
 
Visit Window 
N/A 
N/A 
±1wk 
+1wk 
+1wk 
+1wk 
± 2 days 
± 2 
weeks 
± 3 
months 
Refer to 
Table 4 
± 2 
months 
± 1 
month 
 
Blood sample for rhTSH-
stimulated Tg 
 
 
 
 
 
 
 
 
 
Xa 
 
 
6.4.3.2 
Neck ultrasound 
Xl 
 
 
 
 
 
 
 
X 
X 
 
 
6.4.4.1 
Neck MRI 
Xl 
 
 
 
 
 
 
 
 
Xa 
 
 
6.4.4.3 
Chest CT without contrast 
Xl 
 
 
 
 
 
 
 
 
Xa 
 
 
6.4.4.4 
Final follow-up assessment 
of clinical status 
 
 
 
 
 
 
 
 
 
 
 
X 
6.4.8 
Biopsy/FNA for disease 
confirmation 
 
 
 
 
 
 
 
 
Xm 
Xm 
 
 
6.4.4.5 
Tumour biopsy on 
progression (optional) 
Optional sample on disease progression (for example, if the patient is re-treated for persistent or recurrent thyroid cancer, or has further surgery). 
Note that both a plasma and serum sample for exploratory analysis should also be taken on disease progression. 
6.10.3 
6.10.2  
 
 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
Reason for Amendment:  
Amended to clarify visit window for RAI treatment dose administration, visit 4 and visit 6. 
Section of protocol affected: 
4.1 
Inclusion criteria: 
Previous text: 
14.  Adequate organ function as defined by: 
(a) ANC  1.5x109/L (1500 per mm3) 
(b) Platelets  100 x 109/L (100,000 per mm3) 
(c) Hemoglobin  9 g/dL 
(d) ALT/SGOT and AST/SGPT < 2.5 X upper limit of normal (ULN). 
(e) Bilirubin  1.5 X ULN (with the exception that patients with elevated 
unconjugated bilirubin due to a pre-existing diagnosis of Gilbert’s syndrome are 
eligible for the study) 
(f) Serum creatinine clearance > 50mL/min by either Cockcroft-Gault formula (see 
Appendix E) or 24hr urine collection analysis. 
Revised text: 
14. Adequate organ function as defined by following lab values before randomization: 
(a) ANC  1.5x109/L (1500 per mm3) 
(b) Platelets  100 x 109/L (100,000 per mm3) 
(c) Hemoglobin  9 g/dL 
(d) ALT/SGOT and AST/SGPT < 2.5 X upper limit of normal (ULN). 
(e) Bilirubin  1.5 X ULN (with the exception that patients with elevated 
unconjugated bilirubin due to a pre-existing diagnosis of Gilbert’s syndrome are 
eligible for the study) 
(f) Serum creatinine clearance > 50mL/min by either Cockcroft-Gault formula (see 
Appendix E) or 24hr urine collection analysis. 
Retest is allowed within screening period. 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
14(32) 
Reason for Amendment: 
Amended to specify time frame for assessment of adequate organ function criterion. 
Section of protocol affected: 
4.2 
Exclusion criteria: 
Previous text: 
4.   Previous treatment with 131I (RAI) or external beam radiation therapy (EBRT) at any time 
in the past. 
10.  Patients with clinically significant cardiovascular disease as defined by the following:  
(a) Uncontrolled hypertension (BP 150/95 despite optimal therapy) 
22. Previous enrolment or treatment in the present study. 
Revised text: 
4.  Previous treatment with 131I (RAI) at any time in the past or external beam radiation    
therapy (EBRT) within 6 months before randomization.  
10.  Patients with clinically significant cardiovascular disease as defined by the following:  
(a) Uncontrolled hypertension (at randomization: BP 150/95 despite optimal therapy) 
22. Previous treatment in the present study. 
Reason for Amendment:  
Amended to allow patient’s rescreening, enrolment of patients without EBRT therapy in 6 
months before randomization and specify time frame for assessment of blood pressure and 
adequate organ function criterion.  
Section of protocol affected: 
5.1.2 Other study restrictions 
Previous text: 
                5. Selumetinib capsules contain D-Į- Tocopheryl polyethylene glycol 1000 succinate (TPGS, a 
water-soluble form of vitamin E) as an excipient.  Patients should not therefore 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.  The maximum dose of vitamin E patients 
may receive from selumetinib is approximately 210 mg/day. The concomitant intake of 
excessive (supratherapeutic) doses of vitamin E should be avoided. High doses of vitamin E 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
15(32) 
have been reported to potentiate the anticoagulant activity of coumadins such as warfarin. 
Patients who are taking coumadin anticoagulants should increase the frequency of assessment 
of anticoagulation, such as INR measurements, upon initiation of dosing with study treatment. 
Revised text: 
5.  Selumetinib/placebo capsules contain vitamin E in form of D-Į-tocopheryl polyethlen glycol 
1000 succinate (TPGS), a water-soluble form of vitamin E which acts as a formulation 
excipient. The maximum daily dose of vitamin E that a study subject may receive from 
selumetinib /placebo is approximately 261.6 mg/day. Therefore 
x Patients should not take any supplemental vitamin E. High doses of vitamin E have 
been reported to cause bleeding and interrupt blood coagulation processes. 
x Selumetininb/placebo 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 anticoagulant should be adjusted accordingly. 
Reason for Amendment:  
   The new calculation considers that the selumetinib/placebo capsules contain vitamin E in the 
form of D-Į-tocopheryl polyethylene glycol 1000 succinate (TPGS), a water-soluble form of 
vitamin E.  Intake of selumetinib/placebo capsules may therefore lead to a higher release of 
the active vitamin E. 
Section of protocol affected: 
5.2 Patient enrolment, randomisation and initiation of investigational product 
Previous text: 
The Principal Investigator or delegate will: 
1.  
Obtain signed informed consent from the potential patient before any study specific 
procedures are performed. 
2.  
Determine patient eligibility. See Sections 4.1 and 4.2 
3.  
Call IVRS/IWRS to assign the eligible patient a unique enrolment number  (beginning 
with ‘E#’), and randomisation code (subject number). Randomisation codes will start 
at 001 and go up. 
Randomisation codes will be assigned strictly sequentially by IVRS/IWRS as patients are 
eligible for randomisation. 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
16(32) 
If a patient withdraws from the study, then his/her enrolment/randomisation code cannot be 
reused. 
If a patient withdraws from the study, after they have been enrolled or have received study 
treatment then they cannot re-enter the study. 
Revised text: 
The Principal Investigator or delegate will: 
1.  
Obtain signed informed consent from the potential patient before any study specific 
procedures are performed. 
2.  
Determine patient eligibility. See Sections 4.1 and 4.2 
3.  
Call IVRS/IWRS to assign the eligible patient a unique enrolment number  (beginning 
with ‘E#’), and randomisation code (subject number). Randomisation codes will start 
at 001 and go up. 
Randomisation codes will be assigned strictly sequentially by IVRS/IWRS as patients are 
eligible for randomisation. 
If a patient withdraws from the study, then his/her enrolment/randomisation code cannot be 
reused. 
If a patient withdraws from the study, after they have received study treatment then they 
cannot re-enter the study 
If a patient is re-screened, a new E-code will always be assigned. 
Reason for Amendment: 
To allow patient’s rescreening. 
Section of protocol affected: 
5.3 Procedures for handling patients incorrectly enrolled, randomised or initiated on 
investigational product 
 Previous text: 
Patients who fail to meet the inclusion/exclusion criteria should not, under any 
circumstances, be enrolled or receive study medication.  There can be no exceptions to this 
rule. Patients who are incorrectly enrolled but are not yet randomised or initiated on treatment 
should be withdrawn from the study. 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
17(32) 
Where patients that do not meet the inclusion and/or exclusion criteria, are enrolled in error, or 
incorrectly started on treatment, or where patients subsequently fail to meet the study criteria 
post initiation, the investigator should inform the AstraZeneca Physician immediately.  
 The AstraZeneca Physician must ensure all such contacts are appropriately documented. 
Revised text: 
Patients who fail to meet the inclusion/exclusion criteria should not, under any circumstances, 
be enrolled or receive study medication.  There can be no exceptions to this rule. 
Where patients that do not meet the study criteria are enrolled in error, incorrectly 
randomised, a discussion must occur between AstraZeneca Study Physician and the 
Investigator regarding the patient’s safety and well-being and whether to continue or 
discontinue the patient from the study treatment. The AstraZeneca Study Physician is to 
ensure all such decisions are appropriately documented. In situations where an agreement 
cannot be reached, the patient should have their therapy stopped, then followed up for the 
primary endpoint assessments and safety. Those patient randomised in error should remain in 
the study and be followed for the primary endpoint assessments and safety where possible. 
Reason for Amendment 
Amended to provide clear instruction on handling patients that are incorrectly enrolled, 
randomised or initiated on investigational product. 
Section of protocol affected: 
5.5.3.1 Selumetinib dose reduction or interruption  
Previous text: 
It is essential that patients remain on study treatment continuously for a minimum of 7 
consecutive days prior to their planned RAI therapy, on the day of RAI therapy, and for 5 
consecutive days afterwards.  If necessary, RAI therapy may be rescheduled at the discretion 
of the Investigator until the patient has been on study treatment for a minimum of 7 
consecutive days (as long as the total duration of study treatment does not exceed 43 days, this 
allows the planned RAI to be postponed by up to 1 week if absolutely necessary). 
For all adverse events reported in this study that are considered at least partly causal to 
administration of selumetinib, the following dose modification guidance should be applied.   
Study treatment with selumetinib/placebo should be temporarily interrupted if one of the 
following AEs are observed (and considered causal to study treatment), despite optimal 
supportive care (ie, supportive treatment may be given prior to withholding study treatment): 
• 
Any intolerable adverse event regardless of Grade 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
18(32) 
• 
Any adverse events  CTCAE Grade 3 
On improvement of the adverse event to Grade 1 (Grade 2 for rash) or baseline, study 
treatment may be restarted at the original dose or may be reduced at the discretion of the 
investigator. One dose reduction of study treatment to 50 mg twice daily is permitted before 
permanent discontinuation.   
• 
If a further episode of the same AE subsequently requires dose interruption, 
selumetinib may be restarted at the next dose level down on improvement of the AE. 
• 
If a different AE subsequently requires dose interruption, selumetinib may be restarted 
at the same dose or at the next dose level down on improvement of the AE.   
• 
Selumetinib should not be re-escalated to an earlier dose level on improvement of an 
AE. 
• 
The schedule of assessments described in Table 3 should continue relative to Day 1 in 
the event of selumetinib dose interruption or reduction. 
Therefore, the dose reduction/adjustment algorithm in the study allows for 2 steps only:  
75 mg twice daily (initial dose) 
Ļ 
50 mg twice daily 
Ļ 
permanent discontinuation 
All dose delays, reductions and adjustments will be recorded in the appropriate electronic 
Case Report Form (eCRF). 
The guidance above should also be followed for dose interruptions or reductions for adverse 
events of rashes or diarrhoea. Guidance for interruption or reduction of treatment with 
selumetinib may be considered for particular events, as indicated in the algorithms provided as 
a separate study aid in the “Guidance for Management of Specific Adverse Events in Studies 
of Selumetinib” (refer to Section 5.5.3.2).   
 
Revised text: 
Patients should remain on study treatment continuously for a minimum of 7 consecutive days 
prior to their planned RAI therapy, on the day of RAI therapy, and for 5 consecutive days 
afterwards. If necessary, RAI therapy may be postponed up to 1 week at the discretion of the 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
19(32) 
Investigator to allow the patient receive study treatment for a minimum of 7 consecutive days 
(as long as the total duration of study treatment does not exceed 43 days) 
For all adverse events reported in this study that are considered at least partly causal to 
administration of selumetinib, the following dose modification guidance should be applied.   
Study treatment with selumetinib/placebo should be temporarily interrupted if one of the 
following AEs are observed (and considered causal to study treatment), despite optimal 
supportive care (ie, supportive treatment may be given prior to withholding study treatment): 
• 
Any intolerable adverse event regardless of Grade 
• 
Any adverse events  CTCAE Grade 3 
On improvement of the adverse event to Grade 1 (Grade 2 for rash) or baseline, study 
treatment may be restarted at the original dose or may be reduced at the discretion of the 
investigator. One dose reduction of study treatment to 50 mg twice daily is permitted before 
permanent discontinuation.   
• 
If a further episode of the same AE subsequently requires dose interruption, 
selumetinib may be restarted at the next dose level down on improvement of the AE. 
• 
If a different AE subsequently requires dose interruption, selumetinib may be restarted 
at the same dose or at the next dose level down on improvement of the AE.   
• 
Selumetinib should not be re-escalated to an earlier dose level on improvement of an 
AE.  
• 
The schedule of assessments described in Table 3 should continue relative to Day 1 in 
the event of selumetinib dose interruption or reduction. 
Therefore, the dose reduction/adjustment algorithm in the study allows for 2 steps only:  
75 mg twice daily (initial dose) 
Ļ 
50 mg twice daily 
Ļ 
permanent discontinuation 
If a patient suspends study treatment (selumetinib or placebo) for more than 14 days they are 
no longer eligible to re-start the study treatment. 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
20(32) 
All dose delays, reductions and adjustments will be recorded in the appropriate electronic 
Case Report Form (eCRF). 
The guidance above should also be followed for dose interruptions or reductions for adverse 
events of rashes or diarrhoea. Guidance for interruption or reduction of treatment with 
selumetinib may be considered for particular events, as indicated in the algorithms provided as 
a separate study aid in the “Guidance for Management of Specific Adverse Events in Studies 
of Selumetinib” (refer to Section 5.5.3.2).   
Reason for Amendment:  
Amended to provide clear instruction on allowed IP interruption and treatment plan. 
Section of protocol affected: 
5.6 Concomitant medications 
Previous text: 
x
The maximum dose of vitamin E patients may receive from selumetinib is 
approximately 210 mg/day. The concomitant intake of excessive (supratherapeutic) 
doses of vitamin E should be avoided in patients receiving the capsule formulation. 
Revised text: 
x
The maximum dose of vitamin E patients may receive from selumetinib is 
approximately 261.6 mg/day. The concomitant intake of excessive 
(supratherapeutic) doses of vitamin E should be avoided in patients receiving the 
capsule formulation. 
Reason for Amendment:  
The new calculation considers that the selumetinib/placebo capsules contain vitamin E in the 
form of D-Į-tocopheryl polyethylene glycol 1000 succinate (TPGS), a water-soluble form of 
vitamin E.  Intake of selumetinib/placebo capsules may therefore lead to a higher release of 
the active vitamin E. 
 
Section of protocol affected: 
5.8.1 Procedures for premature discontinuation of a patient from investigational product  
Previous text: 
A patient that decides to prematurely discontinue investigational product will always be asked 
about the reason(s) and the presence of any adverse events.  If possible, they will be seen and 
assessed by an investigator(s).  Adverse events will be followed up (See Sections 6.5.3 and 
6.5.4), and all study drugs should be returned by the patient.  In this situation, a treatment 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
21(32) 
discontinuation visit will be conducted as soon as possible after the patient received the last 
dose of study drug (selumetinb/placebo). A single 12-lead ECG is also required at premature 
discontinuation of treatment. 
If a patient is withdrawn from the study (ie, withdraws consent for follow-up procedures), see 
Section 5.10. 
Collection of all AEs/SAEs will continue until 30 days after the last dose of study drug 
(selumetinib/placebo) for prematurely withdrawn patients. As long as the patient does not 
withdraw consent, follow up in this study will continue as planned. 
Any patient with an AST, ALT or bilirubin value above ULN at time of the last dose of 
selumetinib/placebo should have a further liver chemistry profile (AST, ALT, bilirubin and 
ALP) performed 30 days (±7days) after discontinuation.  
Revised text: 
A patient that decides to prematurely discontinue investigational product will always be asked 
about the reason(s) and the presence of any adverse events.  If possible, they will be seen and 
assessed by an investigator(s).  Adverse events will be followed up (See Sections 6.5.3 and 
6.5.4), and all study drugs should be returned by the patient.  In this situation, a treatment 
discontinuation visit will be conducted as soon as possible after the patient received the last 
dose of study drug (selumetinb/placebo). A single 12-lead ECG, physical examination, vital 
signs measurement, clinical chemistry, haematology is also required at premature 
discontinuation of treatment. As long as the patient does not withdraw consent, study visits 
will be continued according to study plan. RAI treatment will be administered as soon as 
possible after last dose of investigational product and WBS will be performed 3-10 days 
following the RAI dose. 
RAI treatment must be preceded by 0.9 mg intra-muscular injection of thyrogen administered 
2 days immediately prior to RAI. 
30 days post treatment visit will be conducted 30 days (+/- 2days) after last dose of 
investigational product or RAI (whatever latest). The schedule of follow – up assessments 
described in Table 3 should continue relative to RAI treatment in the event of selumetinib 
premature discontinuation. 
A patient that decides to prematurely discontinue investigational product and has not received 
RAI treatment should continue study visits according to study plan. The schedule of follow – 
up assessments described in Table 3 should continue relative to planned date of RAI 
treatment. 
If a patient is withdrawn from the study (ie, withdraws consent for follow-up procedures), see 
Section 5.10. 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
22(32) 
Any patient with an AST, ALT or bilirubin value above ULN at time of the last dose of 
selumetinib/placebo should have a further liver chemistry profile (AST, ALT, bilirubin and 
ALP) performed 30 days (±7days) after discontinuation. 
Reason for Amendment:  
To provide clear and detailed instruction on handling IP discontinued patients.  
Section of protocol affected: 
6.4.4.2 WBS definition of structural DTC 
Previous text: 
The WBS evaluation will be made by blinded, independent central review. 
If the central review determines no visible 131I uptake then the WBS for that patient will be 
considered normal/negative (no disease).  Areas considered to be anatomically normal (for 
example uptake in the salivary glands, stomach, gastrointestinal, urinary tract and bladder) 
will not be considered disease. 
If the central review determines there is a low level of visible uptake in the thyroid bed: 
• 
Uptake must be < 0.1% to be considered normal/negative (no disease). 
• 
If uptake in the thyroid bed region is  0.1%, the patient will be deemed not to be in 
remission due to the presence of iodine-avid DTC. 
The % uptake in the thyroid bed (using the region-of-interest method drawn over the thyroid 
bed) will be measured and calculated by the local Investigator site and entered into the eCRF, 
to be made available to the central reviewer. 
If an abnormality identified by US is subsequently shown to be RAI avid on WBS, the WBS 
data takes precedent over a negative biopsy/FNA 
Revised text: 
The WBS evaluation will be made by blinded, independent central review. 
If the central review determines no visible 131I uptake then the WBS for that patient will be 
considered normal/negative (no disease).  Areas considered to be anatomically normal (for 
example uptake in the salivary glands, stomach, gastrointestinal, urinary tract and bladder) 
will not be considered disease. 
If the central review determines there is a low level of visible uptake in the thyroid bed: 
• 
Uptake must be < 0.1% to be considered normal/negative (no disease). 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
23(32) 
• 
If uptake in the thyroid bed region is  0.1%, the patient will be deemed not to be in 
remission due to the presence of iodine-avid DTC. 
The % uptake in the thyroid bed will be assessed by the local Investigator site according to the 
local clinical practice and entered into the eCRF to be made available to the central reviewer. 
If an abnormality identified by US is subsequently shown to be RAI avid on WBS, the WBS 
data takes precedent over a negative biopsy/FNA 
Reason for Amendment:  
This change has been made in order to reflect the current situation in the clinical practice and 
allows the study to be more breadth in terms of used existing clinical practice approaches. 
Section of protocol affected: 
6.5.5 Laboratory safety assessments  
Previous text: 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
24(32) 
Table 7 
Laboratory safety assessments 
Clinical chemistry 
Haematology 
Urinalysis a 
s-Albumin 
Erythrocyte count 
u-Albumin 
s-ALT 
Haemoglobin 
u-Creatinine 
s-AST 
Platelet count 
 
s-ALP 
Leucocyte cell count 
 
s-Total Calcium 
Leucocyte differential count 
(absolute count): 
 
s-Creatinine 
Neutrophils 
 
s-Gamma glutamyl transferase (JGT) Eosinophils 
 
s-Glucose 
Basophils 
 
s-Magnesium 
Lymphocytes 
 
s-Phosphate 
Monocytes 
 
s-Potassium 
 
 
s-Sodium 
 
 
s-Total protein 
 
 
s-Total bilirubin 
 
 
s-Urea nitrogen 
 
 
s-Creatine kinase 
 
 
a A single-spot urine specimen will be collected on the day of scheduled visit, at sites where the local laboratory 
is able to determine the concentration of urine albumin and urine creatinine from a single-spot urine specimen.  
Investigational sites unable to report these parameters will perform routine urinalysis according to the local 
standard of care.  
s serum 
u urine  
 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
25(32) 
Revised text: 
Table 7 
Laboratory safety assessments 
Clinical chemistry 
Haematology 
Urinalysis a 
s, p-Albumin 
Erythrocyte count 
u-Albumin 
s, p-ALT 
Haemoglobin 
u-Creatinine 
s, p-AST 
Platelet count 
 
s, p-ALP 
Leucocyte cell count 
 
s, p-Total Calcium 
Leucocyte differential count 
(absolute count or percentage): 
 
s, p-Creatinine 
Neutrophils 
 
s, p-Gamma glutamyl transferase 
(JGT) 
  Eosinophils 
 
s, p-Glucose 
Basophils 
 
s, p-Magnesium 
Lymphocytes 
 
s, p-Phosphate 
Monocytes 
 
s, p-Potassium 
 
 
s, p-Sodium 
 
 
s, p-Total protein 
 
 
s, p-Total bilirubin 
 
 
s, p-Urea nitrogen 
 
 
s, p-Creatine kinase 
 
 
a A single-spot urine specimen will be collected on the day of scheduled visit, at sites where the local laboratory 
is able to determine the concentration of urine albumin and urine creatinine from a single-spot urine specimen.  
Investigational sites unable to report these parameters will perform routine urinalysis according to the local 
standard of care.  
s, p serum, plasma 
u urine  
 
Reason for Amendment:  
Amended to allow local laboratories to perform clinical chemistry assessments in plasma and 
provide leucoytes results in percentage.  
 
Section of protocol affected: 
13.1 
Medical emergencies and AstraZeneca contacts 
Previous text: 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
26(32) 
Name  
Role in the study  
Address & telephone number 
Dr Jeffrey Skolnik 
 
AstraZeneca Physician 
responsible for the protocol at 
central R&D site 
 
1800 Concord Pike 
PO Box 15437 
Wilmington DE 19850-5437 
USA 
+1 302 885 7686 (desk) 
+1 302 897 8379 (cell) 
Fax +1 302 886 2622 
Jeffrey.Skolnik@astrazeneca.com 
Dr Marta Bucko-Justyna 
 
AstraZeneca Study Delivery 
Team Leader responsible for the 
protocol at central R&D site 
 
AstraZeneca R&D | Poland Clinical 
Operational Hub 
Postepu 18, Warsaw 02-676, Poland 
+48 22 541 55 96 (desk) 
 +48 600 429 094 (cell) 
Fax: +48 22 541 55 10 
Marta.Bucko-Justyna@astrazeneca.com 
24-hour emergency cover at 
central R&D site. 
 
24-hour emergency cover at 
central R&D site. 
 
Alderley Park 
Macclesfield, Cheshire, SK10 4TG 
 UK 
Contact AZ UK Lt Switchboard Tel: 
+ 44 1625 582828 
 
Revised text: 
Name 
Role in the study 
Address & telephone number 
MD, PhD Raisa 
Kurliandskaya 
 
AstraZeneca Physician 
responsible for the protocol at 
central R&D site 
 
AstraZeneca R&D | Poland Clinical 
Operational Hub 
Postepu 18, Warsaw 02-676, Poland 
+48 22 5415620 (desk) 
+48 696 950 158 (cell) 
Fax +48 22 541 55 10 
Raisa.Kurliandskaya@astrazeneca.com 
 
Linda Fan 
 
 
AstraZeneca Study Delivery 
Team Leader responsible for the 
protocol at central R&D site 
 
AstraZeneca R&D | Clinical Development  
Lane 898, Halei Road, Shanghai,  
China 201203 
+86 21 6030 2288 ext 2725 (desk) 
+86 186-2167-6071 (cell) 
+86 21 50278559 (fax) 
Linda.Fan@astrazeneca.com 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
27(32) 
24-hour emergency cover at 
central R&D site. 
24-hour emergency cover at 
central R&D site. 
Alderley Park  
Macclesfield, Cheshire, SK10 4TG UK 
Contact AZ UK Lt Switchboard  
Tel:+ 44 1625 582828 
 
Reason for Amendment:  
Personnel changes in the Study Team. 
 
Section of protocol affected: 
Appendix G 
Guidance for Management of Adverse Events in Studies of Selumetinib 
2. GUIDANCE FOR MANAGEMENT OF PATIENTS WITH VISUAL SYMPTOMS 
Previous text: 
2. GUIDANCE FOR MANAGEMENT OF PATIENTS WITH VISUAL SYMPTOMS 
 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
28(32) 
 
 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
29(32) 
 
Revised text: 
2. GUIDANCE FOR MANAGEMENT OF VISUAL SYMPTOMS OR ABNORMAL 
FINDINGS 
 
Reason for Amendment:  
Amended to include Retinal Pigment Epithelial Detachment (RPED)   
 
Section of protocol affected: 
Appendix G 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
30(32) 
Guidance for Management of Adverse Events in Studies of Selumutinib 
4. RECOMMENDATIONS FOR INVESTIGATIONS OF PATIENTS WITH NEW OR 
WORSENING DYSPNEA 
Previous text: 
4. RECOMMENDATIONS FOR INVESTIGATIONS OF PATIENTS WITH NEW OR 
WORSENING DYSPNEA 
 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
31(32) 
Revised text: 
4. GUIDANCE FOR MANAGEMENT OF PATIENTS WITH DYSPNOEA 
 
 


Clinical Study Protocol Amendment 3 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Date 01 July 2014 
32(32) 
Reason for Amendment:  
Dyspnoea is an expected event of selumetinib. However dyspnoea could also be the symptom 
of underlying serious lung conditions, e.g. Interstitial Lung Disease (ILD) events.  Although 
no causal relationship has been established between selumetinib and such ILD events, ILD is 
considered as an important potential risk for selumetinib. Therefore, the safety management 
algorithm for dyspnoea allows investigators to diagnose and treat ILD events as early as 
possible, should they occur. 
 
 
 
Persons who initiated the Amendment: 
, Medical Science Director 
, Director Clinical Development 
, Clinical Development Manager 
 
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Clinical Study Protocol Amendment No 3 Appendix 
A 
 
Drug Substance 
Selumetinib (AZD6244) 
 
Study Code 
D1532C00065 
 
Edition Number 
1 
 
Date 
01 July 2014 
 
Protocol Dated 
20 January 2013 
 
 
 
 
 
 
 
 
 
Appendix A 
Signatures 
 


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PROTOCOL SYNOPSIS 
 
A Randomised, Double Blind Study to Compare the Complete Remission 
Rate Following a 5-Week Course of Selumetinib or Placebo and Single Dose 
Adjuvant Radioactive Iodine Therapy in Patients with Differentiated 
Thyroid Cancer 
 
 
International Co-ordinating Investigator  
 
Study centre(s) and number of patients planned 
Approximately 228 patients with newly diagnosed differentiated thyroid cancer at high risk of 
primary treatment failure will be recruited from approximately 50 sites in Europe, South 
and/or North America.     
Objectives 
Primary objectives 
To compare the efficacy of selumetinib with radioactive iodine therapy (RAI), versus placebo 
with RAI, by assessment of complete remission rate at 18 months post RAI treatment in the 
overall study population. Complete remission is defined in Section 6.4.1. 
To compare the efficacy of selumetinib with RAI, versus placebo with RAI, by assessment of 
complete remission rate at 18 months post RAI treatment in a sub-group of patients with 
tumours known to be mutation positive for BRAF or NRAS (defined in Section 6.10.1). 
Complete remission is defined in Section 6.4.1. 
Secondary objectives 
To compare the efficacy of selumetinib with RAI, versus placebo with RAI by assessment of 
clinical remission rate at 18 months post RAI treatment in the overall study population. 
Clinical remission is defined in Section 6.4.6. 
To compare the efficacy of selumetinib with RAI, versus placebo with RAI by assessment of 
clinical remission rate at 18 months post RAI treatment in a sub-group of patients with 
tumours known to be mutation positive for BRAF or NRAS (defined in Section 6.10.1). 
Clinical remission is defined in Section 6.4.6. 
To assess the safety and tolerability of selumetinib with RAI compared to placebo with RAI. 
33'


Clinical Study Protocol Synopsis 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
3(118) 
To investigate the pharmacokinetics (PK) of selumetinib and N-desmethyl selumetinib when 
administered to patients with differentiated thyroid cancer. 
Exploratory objectives 
To explore subsequent thyroid cancer therapy given to patients who receive  selumetinib with 
RAI, or placebo with RAI. 
To investigate the relationship between selumetinib and/or N-desmethyl selumetinib plasma 
concentrations/exposure and clinical outcomes, efficacy, AEs and/or safety parameters. 
To collect tumour, plasma and serum samples for potential future research on biomarkers 
relevant to DTC and response and resistance to study treatments. 
To collect and store DNA for future exploratory research into genes/genetic variation that may 
influence response (ie, distribution, safety, tolerability and efficacy) to selumetinib or RAI 
and/or susceptibility to cancer. 
Study design 
This is a double-blind, randomised, placebo-controlled study comparing the efficacy of a short 
course (approximately 5 weeks) of selumetinib (75 mg, orally twice daily) with adjuvant RAI, 
to placebo with RAI.  
Following recovery from surgery (1 or 2-stage total thyroidectomy), and screening to 
determine study eligibility, patients will be randomised and will take their assigned study 
treatment (selumetinib or placebo) twice daily for a period of approximately 5 weeks.  Study 
treatment will begin approximately 4 weeks prior to the planned day of single dose RAI 
therapy, and will be continuous until 5 days following RAI therapy.  Patients will be required  
to adhere to a standardised low iodine diet prior to their RAI therapy.  For each of the 2 days 
immediately prior to their planned RAI therapy, patients will receive a 0.9 mg intramuscular 
(IM) recombinant human TSH injection (rhTSH, Thyrogen), in order to stimulate iodide 
uptake (patients or clinicians choosing to prepare for RAI ablation by withdrawal of thyroid 
hormone treatment will be ineligible for this study).  Following the 2 consecutive days of 
rhTSH injections, patients will receive their planned RAI therapy as a fixed single 100 mCi 
(3.7 GBq) dose of 131I the immediate next day. Study treatment will be taken as normal on the 
day of RAI therapy, and will be discontinued 5 days following the patient’s RAI therapy. 
Following RAI therapy, each patient will be followed up for a period of 18 months until the 
primary endpoint assessment of complete remission. The biochemical analysis contributing to 
the 18 month primary endpoint of complete remission will be performed by standardised 
central methodology, and the radiological imaging for structural disease at the primary 
endpoint will be subject to a blinded independent central review. Additional thyroid cancer 
therapy (eg, surgery or RAI treatment) must only be given during the 18 month primary 
endpoint follow up period according to the pre-specified study re-treatment criteria (refer to 
Section 5.9). Patients who do receive re-treatment in the 18 months following their initial RAI 


Clinical Study Protocol Synopsis 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
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therapy, will not have any 18 month primary endpoint assessments performed; they will 
remain in the study and enter standard of care follow up according to local practice. 
Following the primary endpoint assessments (or re-treatment), all randomised patients will be 
further followed-up at 3 years after their initial RAI treatment, in order to further assess both 
the clinical status of patients, and the safety profile of selumetinib and RAI beyond the 
primary analysis (refer to Section 6.4.8). 
Target patient population 
Patients with histologically or cytologically confirmed follicular cell derived differentiated 
thyroid cancer (including papillary thyroid cancer and all variants, follicular thyroid cancer 
and all variants, and poorly differentiated thyroid cancer), who are determined to be at high 
risk of primary treatment failure, as defined by any one of the following staging categories 
post-surgery: 
x
Primary tumour greater than 4 cm  
x
Primary tumour of any size with gross extrathyroidal extension outside the thyroid 
gland (T4 disease) 
x
N1a or N1b disease with at least 1 lymph node  1 cm 
x
N1a or N1b disease involving 5 or more lymph nodes (of any size)  
Patients with known distant metastatic disease will be excluded from this study. 
Investigational product, dosage and mode of administration 
Selumetinib Hyd-Sulfate (75 mg) will be administered orally twice daily as capsules (blue).  
The Hyd Sulfate formulation will be used in this study, and unless otherwise specified is the 
formulation referenced throughout this document.  
Comparator, dosage and mode of administration 
Placebo (to match selumetinib) will be administered orally twice daily. 
Duration of treatment 
The duration of study treatment (selumetinib/placebo) will be approximately 5 weeks in total 
(Day 36 will typically be the last day of study treatment, but this may be extended to a 
maximum of 43 days to allow the planned RAI to be postponed by up to 1 week if absolutely 
necessary). 


Clinical Study Protocol Synopsis 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
5(118) 
Outcome variable(s):  
Efficacy 
The primary outcome variable for this study is the rate of complete remission at 18 months 
post-RAI treatment.  Patients will be defined to be in complete remission if all of the 
following criteria can be demonstrated: 
1. 
Serum thyroglobulin (Tg) levels < 1ng/mL during rhTSH stimulation, in the 
absence of interfering Tg antibodies, as assessed by standardised central laboratory 
analysis. 
2. 
No confirmed evidence of thyroid cancera by neck US, as assessed by investigator 
site review. 
3. 
No confirmed radiological evidence of thyroid cancera, as assessed by blinded 
independent central review.  
4. 
No histopathological evidence of thyroid cancer on FNA/biopsy when performed, 
as assessed by investigator site review. 
5. 
No further thyroid cancer therapy was administered in the first 18 months following 
the initial RAI treatment. 
aConfirmation of evidence of structural DTC will be either histopathological (from a 
biopsy/FNA; as criterion 4 above), or RAI-avid disease (refer to Section 6.4.4.2). In this 
disease setting, structural abnormalities that are not RAI-avid and do not have confirmed 
histopathology consistent with DTC (ie are not biopsy proven) are considered benign in the 
absence of biochemical DTC. 
A secondary outcome variable will be the rate of clinical remission at 18 months post-RAI 
treatment, where clinical remission is defined on the basis of Tg, US and WBS assessments 
alone, without the additional radiological data.  
Safety 
AEs/SAEs, physical examination results, lab values, ECG, vital signs. 
All randomised patients will be followed for safety monitoring for 3 years following their RAI 
adjuvant treatment, in order to monitor for selumetinib and RAI-associated side effects. 
PK 
Where sample collection and PK analysis allow, derived PK parameters for selumetinib and  
N-desmethyl selumetinib will be produced which may include, but not be restricted to, Cmax 
and AUC.  Exploratory variables will be analysed outside the clinical study report (CSR). 


Clinical Study Protocol Synopsis 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
6(118) 
Statistical methods 
Approximately 228 patients will be randomised in a 2:1 ratio in this study. The primary 
analysis will be performed when patients have been followed for 18 months following their 
RAI treatment. There will be two primary analysis populations: the first will comprise all 
randomised patients (overall population); the second will comprise the sub-group of 
randomised patients with tumours known to be mutation positive for BRAF or NRAS.  The 
primary endpoint of complete remission rate will be analyzed using a logistic regression 
model with covariates histology status (papillary, follicular, poorly differentiated), mutation 
status (overall population only, BRAF/NRAS positive, BRAF/NRAS negative) and age, 
provided there are enough data points for a meaningful analysis. There will be two primary 
analysis populations: the first will comprise all randomised patients; the second will comprise 
the sub-group of randomised patients with tumours known to be mutation positive for BRAF 
or NRAS. To control the type I error rate for the study and account for the correlation between 
the two primary endpoints, the Dunnett and Tamhane step-up procedure will be used. The 
correlation between the primary endpoint comparisons will be calculated as w, where w is 
the proportion of the overall population who are in the mutation positive sub-group. The 
associated significance level for declaring statistical significance in the mutation positive sub-
group adjusting for this correlation to maintain an overall 5% type I error rate whilst assigning 
4% to the overall population will then be derived. 
Assuming the true complete remission rates in the overall study population are 30% and 50% 
for the placebo and selumetinib-containing arms, respectively, the study will have 80% power 
to demonstrate a statistically significant difference at the 4% (2-sided) significance level.  
Assuming the true complete remission rates in the mutation-positive sub-group are 30% and 
62% for the placebo and selumetinib-containing arms, respectively, the study will have 80% 
power to demonstrate a statistically significant difference at the 1% (2-sided) significance 
level.  
All secondary endpoints will be analysed at the time of the primary analysis. Exploratory 
biomarker analysis may be analysed after the time of the primary analysis and reported 
separately to the CSR (apart from the somatic genetic data required for analysis of the second 
primary endpoint). 
All randomised patients will continue to be followed until the final study visit (3 years after 
their RAI treatment). At this time, data on clinical status, incidence of re-treatment and long-
term safety will be summarised. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
7(118) 
TABLE OF CONTENTS 
PAGE
 
TITLE PAGE...........................................................................................................1 
PROTOCOL SYNOPSIS.........................................................................................2 
TABLE OF CONTENTS.........................................................................................7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................14 
1. 
INTRODUCTION .................................................................................................19 
1.1 
Background............................................................................................................19 
1.1.1 
Thyroid Cancer ......................................................................................................19 
1.1.2 
Radioactive iodine treatment .................................................................................19 
1.1.3 
Risk stratified remission rates following RAI treatment .......................................20 
1.1.4 
The benefits of achieving remission ......................................................................22 
1.1.5 
Selumetinib ............................................................................................................23 
1.1.5.1 
MEK and NIS expression ......................................................................................23 
1.1.5.2 
Clinical data in thyroid cancer ...............................................................................25 
1.1.5.3 
Safety profile of selumetinib..................................................................................26 
1.2 
Research hypothesis...............................................................................................30 
1.3 
Rationale for conducting this study .......................................................................30 
1.4 
Benefit/risk and ethical assessment........................................................................31 
2. 
STUDY OBJECTIVES..........................................................................................31 
2.1 
Primary objectives .................................................................................................31 
2.2 
Secondary objectives .............................................................................................32 
2.3 
Exploratory objectives ...........................................................................................32 
3. 
STUDY PLAN AND PROCEDURES ..................................................................32 
3.1 
Overall study design and flow chart ......................................................................32 
3.1.1 
Treatment Plan.......................................................................................................33 
3.1.2 
Follow-up plan.......................................................................................................34 
3.2 
Rationale for study design, doses and control group .............................................44 
4. 
PATIENT SELECTION CRITERIA.....................................................................46 
4.1 
Inclusion criteria ....................................................................................................46 
4.1.1 
Genetics research study (optional blood sample) ..................................................49 
4.1.2 
Biomarkers research study on tumour progression biopsy....................................49 
4.2 
Exclusion criteria ...................................................................................................49 
4.2.1 
Genetics research study (optional blood sample) ..................................................51 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
8(118) 
5. 
STUDY CONDUCT..............................................................................................52 
5.1 
Restrictions during the study .................................................................................52 
5.1.1 
Low-iodine diet......................................................................................................52 
5.1.2 
Other study restrictions..........................................................................................52 
5.2 
Patient enrolment, randomisation and initiation of investigational product..........53 
5.2.1 
Procedures for randomisation ................................................................................54 
5.3 
Procedures for handling patients incorrectly enrolled, randomised or 
initiated on investigational product........................................................................54 
5.4 
Blinding and procedures for unblinding the study.................................................54 
5.4.1 
Methods for ensuring blinding...............................................................................54 
5.4.2 
Methods for unblinding the study..........................................................................55 
5.5 
Treatments..............................................................................................................55 
5.5.1 
Identity of investigational product(s).....................................................................55 
5.5.2 
Doses and treatment regimens ...............................................................................55 
5.5.3 
Management of study treatment related toxicity ...................................................56 
5.5.3.1 
Selumetinib dose interruption or reduction............................................................56 
5.5.3.2 
Management and investigation of specific selumetinib related AEs.....................57 
5.5.4 
Additional study drugs...........................................................................................58 
5.5.4.1 
Thyrogen (rhTSH, thyrotropin alfa for injection)..................................................58 
5.5.4.2 
Radioactive iodine (RAI).......................................................................................58 
5.5.4.3 
Thyroid hormone supplementation (TSH suppression).........................................58 
5.5.5 
Study drug labelling...............................................................................................59 
5.5.6 
Storage ...................................................................................................................59 
5.6 
Concomitant medications.......................................................................................59 
5.7 
Treatment compliance............................................................................................60 
5.7.1 
Accountability........................................................................................................60 
5.8 
Discontinuation of investigational product............................................................60 
5.8.1 
Procedures for premature discontinuation of a patient from investigational 
product ...................................................................................................................61 
5.9 
Criteria for further thyroid cancer therapy during the study..................................61 
5.9.1 
Re-treatment prior to the 18 month primary endpoint assessments.......................61 
5.9.1.1 
Biochemical disease re-treatment criteria..............................................................62 
5.9.1.2 
Structural disease re-treatment criteria ..................................................................63 
5.9.1.3 
Patient management on study (up to the primary analysis at 18 months 
post-RAI) ...............................................................................................................63 
5.9.2 
Re-treatment after the 18 month primary endpoint assessments ...........................64 
5.10 
Withdrawal from study ..........................................................................................64 
5.11 
Replacement of patients.........................................................................................64 
6. 
COLLECTION OF STUDY VARIABLES...........................................................64 
6.1 
Recording of data...................................................................................................64 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
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6.2 
Data collection at enrolment ..................................................................................64 
6.2.1 
Performance status definitions...............................................................................66 
6.3 
Post-operative imaging assessments for eligibility................................................66 
6.4 
Efficacy..................................................................................................................66 
6.4.1 
Complete remission ...............................................................................................66 
6.4.2 
Staged approach to primary endpoint assessments................................................67 
6.4.2.1 
Primary endpoint assessments Stage 1 ..................................................................70 
6.4.2.2 
Primary endpoint assessments Stage 2 ..................................................................71 
6.4.2.3 
Primary endpoint assessments Stage 3 ..................................................................74 
6.4.3 
Blood sample assessments for efficacy..................................................................74 
6.4.3.1 
Suppressed Tg........................................................................................................74 
6.4.3.2 
Stimulated Tg.........................................................................................................75 
6.4.3.3 
TSH........................................................................................................................75 
6.4.3.4 
Tg antibody (TgAb) ...............................................................................................76 
6.4.4 
Imaging assessments for efficacy ..........................................................................77 
6.4.4.1 
Neck ultrasound (US) ............................................................................................77 
6.4.4.2 
Whole body diagnostic 131I nuclear medicine scan (WBS) ...................................78 
6.4.4.3 
Neck MRI...............................................................................................................79 
6.4.4.4 
Chest CT ................................................................................................................80 
6.4.4.5 
Biopsy or fine needle aspirate (FNA) ....................................................................80 
6.4.4.6 
Information to be sent to the central imaging CRO...............................................81 
6.4.5 
Derivation of primary endpoint of complete remission.........................................82 
6.4.6 
Clinical remission ..................................................................................................84 
6.4.7 
Derivation of clinical remission status...................................................................84 
6.4.8 
Final study follow up at 3 years.............................................................................85 
6.5 
Safety .....................................................................................................................85 
6.5.1 
Definition of adverse events ..................................................................................85 
6.5.2 
Definitions of serious adverse event......................................................................86 
6.5.3 
Recording of adverse events ..................................................................................86 
6.5.3.1 
Disease progression ...............................................................................................89 
6.5.4 
Reporting of serious adverse events.......................................................................89 
6.5.5 
Laboratory safety assessment ................................................................................90 
6.5.6 
Physical examination .............................................................................................91 
6.5.7 
Cardiac monitoring ................................................................................................91 
6.5.7.1 
ECHO or MUGA ...................................................................................................91 
6.5.7.2 
Resting 12-lead ECG .............................................................................................91 
6.5.8 
Vital signs ..............................................................................................................92 
6.5.9 
Other safety assessments........................................................................................92 
6.5.9.1 
Pregnancy test ........................................................................................................92 
6.5.9.2 
Ophthalmologic examination.................................................................................92 
6.6 
Patient reported outcomes (PRO) – not applicable................................................92 
6.7 
Pharmacokinetics ...................................................................................................93 
6.7.1 
PK samples required ..............................................................................................93 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
10(118) 
6.7.2 
Determination of drug concentration.....................................................................93 
6.8 
Pharmacodynamics – not applicable......................................................................93 
6.9 
Pharmacogenetics ..................................................................................................94 
6.9.1 
Genetic blood sample at study entry......................................................................94 
6.10 
Biomarker analysis.................................................................................................94 
6.10.1 
BRAF and NRAS patient population ......................................................................94 
6.10.1.1 Archival tumour sample.........................................................................................94 
6.10.2 
Collection of plasma and serum for exploratory biomarker research....................95 
6.10.3 
Collection of disease progression tumour sample..................................................96 
7. 
BIOLOGICAL SAMPLING PROCEDURES.......................................................97 
7.1 
Volume of blood ....................................................................................................97 
7.2 
Handling, storage and destruction of biological samples ......................................98 
7.2.1 
Pharmacokinetic samples.......................................................................................98 
7.2.2 
Pharmacogenetic samples ......................................................................................98 
7.3 
Labelling and shipment of biohazard samples.......................................................99 
7.4 
Chain of custody of biological samples.................................................................99 
7.5 
Withdrawal of informed consent for donated biological samples .........................99 
8. 
ETHICAL AND REGULATORY REQUIREMENTS.......................................100 
8.1 
Ethical conduct of the study.................................................................................100 
8.2 
Patient data protection..........................................................................................100 
8.3 
Ethics and regulatory review................................................................................100 
8.4 
Informed consent .................................................................................................101 
8.5 
Changes to the protocol and informed consent form...........................................102 
8.6 
Audits and inspections .........................................................................................102 
9. 
STUDY MANAGEMENT BY ASTRAZENECA..............................................102 
9.1 
Pre-study activities...............................................................................................102 
9.2 
Training of study site personnel...........................................................................103 
9.3 
Monitoring of the study .......................................................................................103 
9.3.1 
Source data...........................................................................................................103 
9.4 
Study agreements.................................................................................................104 
9.4.1 
Archiving of study documents.............................................................................104 
9.5 
Study timetable and end of study.........................................................................104 
10. 
DATA MANAGEMENT BY ASTRAZENECA OR DELEGATE....................104 
11. 
EVALUATION AND CALCULATION OF VARIABLES BY 
ASTRAZENECA OR DELEGATE ....................................................................105 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
11(118) 
11.1 
Calculation or derivation of efficacy variable(s) .................................................105 
11.1.1 
Complete remission rate at 18 months post-RAI treatment.................................105 
11.1.2 
Clinical remission rate at 18 months post-RAI treatment....................................105 
11.1.3 
Thyroid cancer recurrence ...................................................................................105 
11.1.4 
Survival status......................................................................................................106 
11.1.5 
Further therapy.....................................................................................................106 
11.2 
Calculation or derivation of safety variable(s).....................................................106 
11.2.1 
Adverse events.....................................................................................................106 
11.2.2 
Other significant adverse events (OAE) ..............................................................106 
11.2.3 
Vital signs, laboratory data, ECGs, ECHO/MUGA, physical examination 
and ophthalmologic examination.........................................................................107 
11.3 
Calculation or derivation of PK variables............................................................107 
11.4 
Calculation or derivation of pharmacogenetic variables......................................107 
11.5 
Calculation or derivation of biomarker variables ................................................108 
11.5.1 
Analysis of NRAS and BRAF ...............................................................................108 
11.5.2 
Further biomarker research analysis ....................................................................108 
12. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION..........108 
12.1 
Description of analysis sets..................................................................................108 
12.1.1 
Intention to treat (ITT) analysis set......................................................................108 
12.1.2 
BRAF/NRAS mutation positive analysis set.........................................................108 
12.1.3 
Treatment-compliant (TC) analysis set................................................................108 
12.1.4 
Safety analysis set................................................................................................108 
12.1.5 
PK analysis set .....................................................................................................109 
12.2 
Methods of statistical analyses.............................................................................109 
12.2.1 
Complete remission rate at 18 months post-RAI treatment.................................109 
12.2.2 
Clinical remission rate at 18 months post-RAI treatment....................................111 
12.2.3 
Thyroid cancer recurrence ...................................................................................111 
12.2.4 
Survival status......................................................................................................111 
12.2.5 
Further therapy.....................................................................................................111 
12.2.6 
Safety data analysis..............................................................................................111 
12.2.7 
PK data analysis...................................................................................................111 
12.2.8 
Genetics................................................................................................................111 
12.2.9 
Biomarker data.....................................................................................................111 
12.2.10 
Interim analyses ...................................................................................................112 
12.3 
Determination of sample size...............................................................................112 
12.4 
Data monitoring committee .................................................................................112 
13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR ................................................................................................113 
13.1 
Medical emergencies and AstraZeneca contacts .................................................113 
13.2 
Overdose ..............................................................................................................113 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
12(118) 
13.3 
Pregnancy.............................................................................................................114 
13.3.1 
Maternal exposure................................................................................................114 
13.3.2 
Paternal exposure.................................................................................................114 
14. 
LIST OF REFERENCES.....................................................................................115 
 
LIST OF TABLES 
Table 1 
Remission rates in 2 independent data sets of risk-categorised 
patients with differentiated thyroid cancer - based on tumour size 
and lymph node status ..............................................................................21 
Table 2 
Example study treatment plan ..................................................................34 
Table 3 
Study Plan.................................................................................................37 
Table 4 
Study Plan for the 18 month Primary Endpoint Assessments..................42 
Table 5 
Criteria for biochemical decision making (based on standardised 
central analysis results).............................................................................73 
Table 6 
Programmatic derivation of complete remission status............................83 
Table 7 
Laboratory safety assessments .................................................................90 
Table 8 
Biomarker summary table ........................................................................97 
Table 9 
Volume of blood to be drawn from each patient......................................97 
 
LIST OF FIGURES 
Figure 1 
Study flow chart .......................................................................................36 
Figure 2 
Time course to achieving a suppressed Tg<1 ng/mL in patients 
receiving total thyroidectomy and RAI therapy .......................................45 
Figure 3 
Flow chart for staged primary endpoint assessments...............................69 
 
LIST OF APPENDICES 
 
Appendix A  
Signatures 
Appendix B  
Additional Safety Information 
Appendix C  
IATA 6.2 Guidance document 


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Appendix D  
Actions Required in Cases of Combined Increase of Aminotransferase and 
Total Bilirubin – Hy’s Law 
Appendix E  
Cockcroft-Gault Formula 
Appendix F 
Low Iodine Diet 
Appendix G  
Guidance for Management of Adverse Events in Studies of Selumetinib 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
124I 
Iodine-124 
131I 
Iodine-131 (radioactive iodine; RAI) 
AE 
Adverse event (see definition in Section 6.5.1) 
AJCC 
American Joint Committee on Cancer 
ALP 
Alkaline phosphatise 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
ATA 
American Thyroid Association 
ATC 
Anaplastic thyroid cancer 
AUC 
Area under the plasma concentration-time curve from zero to infinity 
BD 
Twice daily (dosing) 
bid 
bis in die – twice a day 
BNP 
B-type natriuretic peptide 
BP 
Blood pressure 
Bpm 
Beats per minute 
BRAF 
v-raf murine sarcoma viral oncogene homolog B1 
cm 
centimetres 
Cmax 
Maximum plasma concentration 
CRF 
Case report form (electronic/paper) 
CR 
Clinical remission 
CR 
Complete remission 
CSA 
Clinical study agreement 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse event 
DAE 
Discontinuation of investigational product due to adverse event 
DNA 
Deoxyribonucleic acid  
DTC 
Differentiated thyroid cancer 
D-TC-FCO 
Differentiated thyroid carcinoma of follicular cell origin 


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Abbreviation or 
special term 
Explanation 
DUS 
Disease under study 
EBRT 
External beam radiation therapy 
EC 
Ethics committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
ERK 
Extracellular signal-regulated kinases 
ETA 
European Thyroid Association 
FDG-PET 
2-[F-18]-fluoro-2-deoxy-D-glucose positron emission tomography 
FNA 
Fine needle aspiration 
FSH 
Follicle stimulating hormone 
FTC 
Follicular thyroid cancer 
G1 
Gap 1 phase of the cell cycle 
GCP 
Good clinical practice 
g/dL 
grams per decilitre 
GMP 
Good manufacturing practice 
hr 
hour 
I 
Iodine 
IATA 
International Air Transport Association 
IB 
Investigator brochure 
ICH 
International Conference on Harmonisation 
ICH M3 
The European Medicines Agency’s International Conference on Harmonisation 
Topic M3 – “Non-Clinical Safety Studies for the Conduct of Human Clinical Trials 
and Marketing Authorization for Pharmaceuticals” 
IM 
Intramuscular 
INR 
International normalised ratio 
International 
Co-ordinating investigator 
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or activities 
internationally.  
IP 
Investigational product  
ITT 
Intention-to-treat 
IUD 
Intrauterine device 
IV 
Intravascular 
IVRS 
Interactive voice response system 


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Abbreviation or 
special term 
Explanation 
IWRS 
Interactive web response system 
kg 
kilograms 
KRAS 
v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 
LH 
Luteinizing hormone 
LIMS 
Laboratory information management system 
LLOQ 
Lower limit of quantification 
LSLV 
Last patient last visit 
LT4 
Synthetic levothyroxine 
LV 
Left ventricular 
LVEF 
Left ventricular ejection fraction 
M0, M1, Mx  
Distant metastasis status (TNM cancer staging system) 
MAPK 
Mitogen-activated protein kinase 
mCi 
millicuries 
MedDRA 
Medical dictionary for regulatory activities 
MEK 
MAPK/ERK kinase 
MI 
Myocardial infarction 
Pg/L 
micrograms per litre 
Pm 
micrometers 
mIU/L 
milli-International units per litre 
mg 
milligrams 
mg/day 
milligrams per day 
mL 
millilitres 
mL/min 
millilitres per minute 
mm 
millimetres 
mm3 
cubic millimetres 
ms 
milliseconds 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
MSKCC 
Memorial Sloan Kettering Cancer Center 
MTD 
Maximum tolerated dose 
MUGA 
Multi-gated acquisition scan 
N0, N1, Nx etc 
Lymph node disease stage (TNM cancer staging system) 
N/A 
Not applicable 
ng/mL 
nanograms per milliliter 


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Abbreviation or 
special term 
Explanation 
NIS 
Sodium iodide symporter 
NOEL 
No observed effect level 
NSCLC 
Non-small cell lung cancer 
NTRK 
Neurotrophic tyrosine kinase, receptor, type 1 
NYHA 
New York Heart Association 
OAE 
Other significant adverse event (see definition in Section 6.5) 
PDTC 
Poorly differentiated thyroid carcinomas 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PGx 
Pharmacogenetic research 
PI 
Principal investigator  
PK 
Pharmacokinetics 
PRO 
Patient reported outcomes 
PTC 
Papillary thyroid cancer 
RAI 
Radioactive iodine (131I) 
RET 
Ret proto-oncogene 
Rb 
Retinoblastoma protein 
RECIST 
Response Evaluation Criteria In Solid Tumours 
rhTSH 
Recombinant human thyroid stimulating hormone 
SAE 
Serious adverse event (see definition in Section 6.5.2). 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis software 
SBE-CD 
Sulphobutylether ȕ-cyclodextrin 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
SUV 
Standard uptake value 
T0, T1, Tx etc 
Primary tumour disease stage (TNM cancer staging system) 
T4 
Free thyroxine 
Tg 
Thyroglobulin 
TgAb 
Thyroglobulin antibody 
TNM 
Tumour, nodes, metastasis cancer staging system 
TPGS 
D-Į tocopheryl polyethylene glycol 1000 succinate 


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Abbreviation or 
special term 
Explanation 
TPO 
Thyroid peroxidase 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
US 
Ultrasound 
WBDC 
Web based data capture 
WBS 
Whole body scintigraphy (also whole body scan) 
WHO 
World Health Organisation 
Wk 
Week 
 


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1. 
INTRODUCTION 
1.1 
Background 
1.1.1 
Thyroid Cancer 
There are approximately 56,500 new cases of thyroid cancer diagnosed in the USA per year, 
and approximately 34,000 new cases diagnosed in Europe per year.  Thyroid cancers are 
classified according to their histopathological characteristics into 4 main variants: papillary 
thyroid cancer (PTC, the most common), follicular thyroid cancer,  medullary thyroid cancer 
and anaplastic (undifferentiated) thyroid cancer.  The papillary and follicular types together 
can be classified as differentiated thyroid cancer (DTC), and make up approximately 95% of 
thyroid cancers. All DTC (including PTC) begins in the follicular cells of the thyroid gland 
and is termed “of follicular cell origin.”  Other, rarer variants of thyroid cancer of follicular 
cell origin include Hürthle cell carcinoma and poorly differentiated thyroid cancer (PDTC). 
DTC is generally indolent and has a natural history which is measured in decades if treated 
appropriately (up to 95% 10 year survival). However there are very limited options for 
patients who ultimately fail radioactive iodine therapy and develop distant refractory 
metastases, and most of these patients will succumb to their disease (Durante et al 2006).  
1.1.2 
Radioactive iodine treatment  
In addition to primary thyroid surgery, radioactive iodine (RAI, 131I) is the mainstay of 
therapy for patients with thyroid cancer of follicular origin. It is a targeted therapeutic 
approach that exploits the expression of the sodium iodide symporter (NIS) to deliver 
radiation selectively to thyroid cells, which is used as adjuvant therapy after thyroidectomy, 
and to treat recurrent and metastatic disease.   
Most patients with thyroid cancer of follicular origin have differentiated carcinomas which 
retain at least to some extent the biological properties of normal thyroid cells, including 
expression of NIS. Presence of this transporter is required for iodine uptake (Riesco-
Eizaguirre et al 2006). 
Following diagnosis, surgical resection of the thyroid gland with or without removal of the 
local lymph nodes is performed. Following surgical resection, a set of clinical-pathologic data 
(such as age at diagnosis, specific histological type, size of the primary tumour, extent of 
lymph node metastases, presence of distant metastases, gross extrathyroidal extension and 
completeness of resection) can be used to estimate the risk of recurrence and the risk of 
disease specific mortality. After surgery, radioactive iodine can be used for the following 
purposes: 
For diagnostic scanning to improve initial staging and extent of disease assessment. 
For ablation of the normal thyroid remnant (usually less than 2-3% of normal tissue remains 
after total thyroidectomy). This treatment facilitates follow-up by achieving an undetectable 
level of serum thyroglobulin and a subsequent negative diagnostic whole body RAI scan. 


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As adjuvant therapy, in an attempt to destroy microscopic residual disease in patients at 
intermediate to high risk of recurrence. 
As primary therapy in patients with unresectable RAI-avid loco-regional disease or distant 
metastases.   
Uptake of RAI by tumour tissue is a prerequisite for administration of RAI treatment and for 
its efficacy. Once patients develop distant metastatic disease, RAI uptake is observed in only 
two thirds of cases and less frequently in patients with aggressive disease (Durante et al 2006, 
Mazzaferri and Kloos 2001, Nemec et al 1979, Samaan et al 1985).  Patients with no uptake in 
metastatic foci are considered refractory to RAI, which is then no longer indicated. 
1.1.3 
Risk stratified remission rates following RAI treatment 
Several different risk stratification systems have been published for DTC.  The Union 
Internationale Contre le Cancer/American Joint Committee on Cancer (AJCC) staging system 
is the most commonly used, but it was developed to predict the risk of death rather than 
recurrence.  To overcome this limitation, the American Thyroid Association (ATA) published 
guidelines to grade the risk of recurrence into 3 categories (low, intermediate, and high) based 
on tumour-related parameters (pathological tumour-node-metastasis and histological variant) 
integrated with other clinical features, including the result of the first post-therapy RAI whole-
body scan and serum Tg measurement.  Although the ATA risk stratification system has been 
shown to better predict short-term clinically relevant endpoints of persistent and recurrent 
disease than the AJCC system, it does not adequately predict longer-term outcomes because 
the risk of persistent or recurrent disease changes following initial therapy. In addition, the 
ATA intermediate risk category includes a wide variety of potential risk factors that can have 
a significant influence on both short term and long-term outcomes (any tumour size, N1a/N1b 
node status, vascular invasion, extrathyroidal extension, aggressive histology).  
Recent evidence suggests that the likelihood of achieving remission varies depending on the 
size of the primary tumour, extent of invasion, or lymph node status as defined by number and 
size of affected nodes (refer to Table 1, Tuttle, unpublished sub-analysis of data from Tuttle et 
al 2010 and Vaisman et al 2012). 


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Table 1 
Remission rates in 2 independent data sets of risk-categorised patients 
with differentiated thyroid cancer - based on tumour size and lymph 
node status 
TNM 
status 
Description 
Remission ratea 
MSKCCb 
n=588 patients 
Remission ratea 
Brazilc 
n=506 patients 
T1 
Tumour diameter 2 cm or smaller 
40% 
59% 
T2 
Tumour diameter 2 - 4 cm 
47% 
52% 
T3 
Tumour diameter > 4 cm or with minimal extrathyroidal 
extension 
25% 
37% 
T4 
Tumour of any size extending to invade subcutaneous soft 
tissues, larynx, trachea, esophagus, recurrent laryngeal 
nerve, prevertebral fascia or encasing carotid artery or 
mediastinal vessels 
13% 
17% 
N0 
No metastatic nodes identified 
62% 
54% 
N1a 
Metastatic nodes in central neck (pretracheal, 
paratracheal, or prelaryngeal) 
31% 
30% 
N1b 
Metastatic nodes in lateral neck or superior mediastinum 
16% 
12% 
a Remission rate within a 2 year follow up period 
b unpublished sub-analysis of data from Tuttle et al 2010 
c unpublished sub-analysis of data from Vaisman et al 2012 
As can be seen patients with either T3 disease or N1a disease have remission rates that 
approximate 30%, while patients with T4 disease or N1b disease have remission rates that 
approximate 15%.  From a clinical perspective, these findings are not surprising since T3 
disease is very commonly associated with N1a disease, and T4 disease is often associated with 
N1b disease.  Therefore, the similarity in remission rates in T3 and N1a disease, and in T4 and 
N1b disease, is consistent with observations in clinical practice.   
It is important to note that in addition to the location of the lymph node metastases (N1a vs. 
N1b), the extent of lymph node metastases (size and number of involved nodes) is also a 
critical factor in assessing the risk of recurrence and risk of failing initial therapy (Randolph et 
al, 2012, Ricarte-Filho et al 2012). The complete remission rates from the MSKCC and 
Brazilian cohorts are based on patients with clinically significant, structurally evident N1a 
and/or N1b disease that required therapeutic neck dissections for clinically apparent metastatic 
disease (prophylactic neck dissections to remove sub-clinical disease were not performed in 
either the MSKCC or Brazilian cohorts).  For example, in a MSKCC series of 246 papillary 
thyroid cancer patients who presented with lymph node metastases at the time of diagnosis, a 
median of 6 metastatic lymph nodes were identified with a median maximal diameter of 1.3 
cm (Ricarte-Filho et al 2012).  Furthermore, multiple studies have demonstrated that small 
volume lymph node metastases which are usually identified as incidental findings in the 
fibroadipose tissue surrounding the thyroid, or as a result of prophylactic central neck 
dissections, are associated with a low risk of recurrence (Randolph et al, 2012, Ricarte-Filho 
et al 2012), and these may not even require RAI adjuvant therapy (and therefore would not be 


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appropriate subjects for the proposed study).  Therefore, to prevent patients with lower risk 
N1a or N1b small volume metastatic disease from enrolling into this study, a requirement is 
that subjects must have N1a or N1b disease involving 5 or more lymph nodes (of any size) or 
at least 1 lymph node  1 cm in the largest diameter. 
Since only approximately 30% of patients presenting with any of the following features are 
expected to achieve clinical remission following total thyroidectomy and RAI remnant 
ablation, they are at high risk of failing their primary treatment: 
x
Primary tumour greater than 4 cm 
x
Primary tumours of any size with gross extrathyroidal extension outside the thyroid 
gland (T4 disease) 
x
N1a or N1b disease with at least 1 lymph node  1 cm 
x
N1a or N1b disease involving 5 or more lymph nodes (of any size) 
Total thyroidectomy and RAI ablation is therefore very effective at inducing remission in low 
risk patients, however approximately 70% of patients with the above characteristics do not 
enter remission, and have an incomplete response to initial therapy with biochemical and/or 
structural evidence of persistent disease. 
1.1.4 
The benefits of achieving remission 
Thyroid cancer deaths are exceedingly rare if remission is achieved, and studies have shown 
that nearly all deaths ultimately occur in the group of patients who do not achieve remission. 
For example, two recent studies reported disease-specific deaths in 6% and 8% of the patients 
who did not achieve remission compared to 0% in patients who achieved remission with 
median follow-up times of 7 and 10 years respectively (Tuttle RM, unpublished sub-analysis 
of data from Tuttle et al 2010, Vaisman et al 2012).  This mortality rate continues to rise with 
longer periods of follow up with nearly all deaths from thyroid cancer being seen in the cohort 
of patients that failed to achieve remission.   
The importance of a successful initial therapy is demonstrated by the excellent prognosis that 
even high-risk patients have if therapy results in negative imaging and negative thyroglobulin 
levels after stimulation by TSH. The majority of patients who achieve remission do not 
relapse; recurrence rates are typically 1% to 4% over median follow-up periods of 5 to 10 
years for patients who achieve remission (Castagna et al 2011, Tuttle et al 2010, Vaisman et al 
2012).     
In patients that achieve remission, there are important clinical and psychological benefits. 
Patients that achieve remission are re-classified as low risk patients and require much less 
frequent follow-up. Thyroglobulin testing and imaging assessments are reduced in frequency, 
and less aggressive TSH suppressive therapy is required. This in turn reduces the longer-term 
risks of osteoporosis and atrial fibrillation that are known complications of supra-


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physiological dosing of levothyroxine, and reduces the anxiousness and fatigue that can result 
from the mildly hyperthyroid state caused by TSH suppression. 
If remission is not achieved with initial therapy, many patients will be subjected to additional 
therapies (eg, more RAI, surgery, external beam irradiation), in an effort to control disease 
progression and achieve a cure.  Therapeutic RAI is associated with a cumulative dose-related 
risk of early and late-onset complications such as salivary gland damage, dental caries, 
nasolacrimal duct obstruction, and decreased fertility (Cooper et al 2009). Furthermore, a 
dose-dependent relationship is also seen between cumulative administered RAI activity and 
the subsequent occurrence of secondary malignancies (Rubino et al 2003, Sawka et al 2009). 
All of these risks and symptoms constitute significant quality of life issues for the patient. The 
inconvenience of repeating a low iodine diet, the associated radiation safety precautions and 
missed days of work are additional factors the patient must consider.  Additional surgery 
carries associated risks related to anesthesia, nerve damage (resulting in hoarseness, 
permanent tracheotomy in rare occasions, drooping eye lid, loss of control of shoulder 
muscles and loss of sensation in the neck), increased scarring in the neck (resulting in 
discomfort and difficulty swallowing), and damage to the parathyroid glands (resulting in 
hypocalcemia and a lifetime need for vitamin D and calcium supplementation and frequent 
blood tests). Thus avoidance of further therapy is beneficial to the patient. 
Unfortunately, additional therapy is often less effective, particularly in patients with persistent 
structural disease (Vaisman et al, 2011). Further RAI can be given to patients that have 
persistent biochemical evidence of disease, and although repeat RAI is often less effective 
than the initial RAI treatment (especially for patients with persistent structural disease), it can 
be effective at driving some patients with persistent biochemical disease into remission. Thus, 
strategies designed to improve the tumouricidal effect of the initial RAI dose should result in 
higher remission and cure rates. 
An intervention that enhances the effectiveness of initial therapeutic RAI in higher risk 
patients (the target population for this study), should result in higher remission rates and 
remove the need for further therapy, and would thus be of clear benefit to patients. 
1.1.5 
Selumetinib 
Selumetinib is a potent, selective, noncompetitive inhibitor of MEK, licensed for development 
by AstraZeneca Pharmaceuticals from Array BioPharma.  Selumetinib was discovered by 
Array Biopharma and had the designation ARRY 142886.  Other laboratory code names used 
during the development of this molecule are AR00142886 and AR-142886-X (where X refers 
to a sequential lot number).  Array BioPharma was responsible for the first-into-human study; 
the remainder of the clinical development programme for oncology indications is the 
responsibility of AstraZeneca.  AZD6244 has now been assigned the international non-
proprietary name selumetinib.   
1.1.5.1 
MEK and NIS expression  
Papillary thyroid cancer (PTC), which is the most common form of the disease, is 
characterised by a set of genetic alterations, all of which result in the activation of 


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RAF/MEK/ERK signalling. Of these genetic lesions the most common is the typical V600E 
mutant of BRAF also found in other cancers, most notably melanoma. The other genetic 
lesions occur in receptor tyrosine kinases (RET and NTRK1), and in RAS (N and HRAS). In 
total these mutations in effectors of ERK signalling account for approximately 70% of 
papillary thyroid cancer (Kimura et al 2003, Soares et al 2003). BRAF itself is seen in at least 
38% of PTC, and is also found in poorly differentiated and anaplastic thyroid carcinomas with 
a prevalence of 12% and 50%, respectively (Nikiforova et al 2003, Ricarte-Filho et al 2009). 
These genetic mutations are mutually exclusive and suggest the importance of 
RAF/MEK/ERK signalling in papillary thyroid cancer.  
With regard to the impact on efficacy of RAI therapy, one of the primary effects of activation 
of the RAF/MEK/ERK signalling pathway is a significant and sustained down regulation of 
the sodium iodide symporter (NIS) which is responsible for the uptake of iodine into thyroid 
cells and is required for the uptake of therapeutic 131I into thyroid cancer cells. Studies have 
demonstrated that the expression of NIS (and other genes typical of differentiated thyroid 
cells) is suppressed by activation of RAF/MEK/ERK signalling in mouse models of the 
disease (Franco A et al. 2011). In mice engineered to express V600E BRAF in thyroid cells, 
expression of NIS and other thyroid differentiation markers is reduced (Knauf et al 2005). 
These mice develop papillary thyroid cancers with dedifferentiated features. Further data 
using a mouse model of thyroid-specific inducible expression of V600E BRAF, show that 
V600E BRAF activation suppresses expression of NIS, thyroid peroxidase (TPO) and 
thyroglobulin (Tg), and blocks 124I uptake, all of which are re-established once expression of 
oncogenic BRAF is turned off. Treatment of mice expressing the induced V600E BRAF with a 
MEK inhibitor also re-established NIS expression and 124I uptake in the poorly differentiated 
thyroid carcinomas (PDTC) (Chakravarty D et al 2011). Constitutive activation of MAPK 
signalling also inhibits the expression of thyroid peroxidase and thyroglobulin in BRAF-
induced murine thyroid cancers. Genetic or pharmacological blockade of the pathway restores 
their expression, and consequently the ability to incorporate iodine into tyrosine (iodine 
organification), which is associated with greater retention time of 131I in cancer cells 
(Chakravarty D et al 2011). Other MAPK activating alterations common to thyroid cancer can 
also cause de-differentiation.  Over-expression of either the G12V HRAS mutant or RET/PTC 
in thyroid cancer cells suppresses NIS, thyroglobulin and thyroid peroxidase expression, 
which is restored with MEK inhibitor treatment (Knauf et al 2003, De Vita et al, 2005).  These 
experiments provide a pre-clinical proof of concept that inhibition of ERK signalling by MEK 
inhibitors can reverse the suppression of NIS, TG and TPO expression and re-establish iodine 
incorporation into PTC. 
NIS expression in clinical thyroid cancer samples 
Analysis of clinical tumour samples for NIS expression indicates a relative loss of NIS 
expression (and the expression of other thyroid specific genes) relative to normal thyroid 
tissue (Durante et al 2007; Espadinha et al 2009). Furthermore, NIS expression is lower in 
BRAF mutant tumours than in those without BRAF mutation (Durante et al 2007; Morai et al 
2011; Romei et al 2008).  In a well differentiated rat thyroid cell line model, expression of 
RET/PTC, mutant HRAS, or constitutively active MEK1, blocked TSH-induced expression of 
Tg and NIS; an effect that was reversed by MEK inhibition.  These data are consistent with 


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the hypothesis that activation of MEK, regardless of the upstream activating mutation is a key 
factor in the loss of thyroid differentiation specific gene expression including NIS (Knauf et al 
2003). 
In summary, this data predicts that both an unselected and genetically selected population may 
benefit from treatment with a MEK inhibitor and RAI. This study will thus assess two 
populations for the primary endpoint of complete remission rate at 18 months; the genetic ‘all 
comer’ population, and also a population of patients with tumours carrying BRAF or NRAS 
mutations, as these are known to constitutively activate the MEK signalling pathway. 
Treatment with a MEK inhibitor may thus be hypothesised to deliver a greater treatment effect 
in these patients. However, the pathway can be activated in many ways such that other 
patients may also benefit.  
1.1.5.2 
Clinical data in thyroid cancer 
The preclinical data generated to date suggests the clinical hypothesis that MAPK pathway 
inhibition in patients with RAI-refractory tumours will result in reacquisition of RAI uptake 
and renewed susceptibility to therapeutic 131I.  To test this hypothesis, an investigator-
sponsored selumetinib pilot study has been performed at MSKCC for patients with RAI-
refractory recurrent or metastatic differentiated thyroid carcinoma of follicular cell origin 
entitled, “Reacquisition Of RAI Uptake Of RAI-Refractory Metastatic Thyroid Cancers By 
Pre-treatment With The Selective MEK Inhibitor Selumetinib: A Pilot Study” (Ho et al 2012).  
In this study, the RAI avidity of thyroid tumours was quantified by lesional dosimetry with 
124I PET imaging in patients, before and after 4 weeks of treatment with selumetinib.  For 
patients whose tumours reacquired the ability to take up RAI, 131I treatment was administered, 
and tumour response was assessed both radiographically and with measurement of the serum 
tumour marker thyroglobulin (Tg).   
20 patients were treated with selumetinib in this pilot study.  Of the 20 patients, 9 patients had 
tumours with the V600E BRAF mutation, 5 patients had tumours with NRAS mutations at 
codon 61, 3 patients had tumours with RET/PTC rearrangements, and the remaining 3 patients 
were wild-type for these alterations. Twelve of the 20 patients in the study demonstrated 
increased tumoural 124I uptake, and 8 of these 12 patients achieved sufficient iodine reuptake 
to warrant treatment with 131I.  Interestingly, 5 of these patients were found to have NRAS 
mutations, one a BRAF mutation, one a RET/PTC rearrangement and one patient was wild-
type.  Further genotyping and cytogenetic analysis is ongoing to discover other potential 
oncogenic drivers that may have promoted susceptibility to this therapeutic strategy.  The 
increased iodine incorporation as quantified on the 124I scans translated to clinical efficacy 
with RAI therapy.  Reduction in tumour size by RECIST criteria was achieved in all RAI-
treated patients, with 5 confirmed partial responses and 3 patients with stable disease.  
Substantial decreases in serum thyroglobulin following RAI therapy were achieved in all 8 
RAI-treated patients.  The mean percent reduction in serum thyroglobulin achieved “post-
RAI” (2 months after RAI treatment) compared to “pre-RAI” (within 3 weeks before RAI 
treatment) was 89%.     


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Data from the pilot study also suggests that pre-treatment with selumetinib selectively 
increased RAI uptake in tumoural lesions compared to non-thyroidal tissue (salivary gland). 
This pilot study demonstrates that MAPK pathway inhibition can modulate RAI uptake in the 
most difficult clinical scenario: patients with resistance to RAI therapy. Most patients in the 
pilot clinical study described above had many metastatic lesions, some of which were 
refractory to RAI at baseline, and some of which were partially RAI avid at baseline.  
Importantly, selumetinib not only restored RAI uptake in previously refractory lesions, but 
also increased RAI uptake in most partially-avid lesions (typically by more than 100% 
compared to the baseline value; 3 to 7 fold increases in maximum SUVs in such lesions were 
consistently observed). This provides a strong rationale to develop this strategy in the adjuvant 
setting for RAI naïve patients, with the goal of further enhancing what is more likely to be 
RAI-susceptible disease for patients at high risk of primary treatment failure.    
In addition to the pilot study described above, a phase II study of 100 mg bid selumetinib 
(previous mix-and-drink formulation) in 39 patients with RAI-refractory differentiated 
metastatic thyroid cancer has also been completed (Hayes et al 2012). This study involved 
continuous monotherapy dosing of selumetinib and no RAI treatment. The results 
demonstrated few clinical responses (one partial response in 32 evaluable patients), but 
demonstrated a 66% stable disease rate; median PFS in this poor-prognosis cohort was 
33 weeks in patients with mutations in BRAF V600E, and 32 weeks in all-comers. Although 
this study was conducted with the mix and drink formulation (from which selumetinib 
exposure may be lower), the efficacy of selumetinib as monotherapy in this population was 
disappointing. 
Taken together, these data suggest a strong rationale for investigating selumetinib with RAI in 
patients with DTC.  Given the known prevalence of MEK pathway activation in patients with 
DTC, and both the pre-clinical and clinical data seen when selumetinib is added to RAI, 
increasing iodine uptake, specifically with respect to selumetinib’s ability to upregulate NIS 
expression, adding selumetinib to standard of care RAI treatment has the potential to provide 
important clinical benefit.  This benefit may extend to all patients regardless of their genotype, 
or it may be greater in those patients with tumours driven by mutations in the MEK pathway. 
This study will allow these hypotheses to be tested. 
1.1.5.3 
Safety profile of selumetinib 
Array BioPharma was responsible for the first study of selumetinib into patients.  The 
remainder of the oncology clinical development programme is the responsibility of 
AstraZeneca.  Selumetinib is currently in phase II development, and has been used as both 
monotherapy and in combination with other anti-cancer agents, in a variety of adult solid 
tumour settings (eg, pancreatic cancer, colorectal cancer, melanoma and NSCLC), and 
paediatric cancer patients. 
The formulation taken into the phase I clinical programme by Array Biopharma was an 
extemporaneous preparation of an oral suspension of selumetinib as the free-base in an 
aqueous solution of sulphobutylether ȕ-cyclodextrin (SBE-CD, Captisol®), referred to as the 
free-base suspension formulation (mix and drink).  The AstraZeneca phase II monotherapy 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
27(118) 
clinical programme also utilised this formulation.  Subsequent formulation development 
resulted in a capsule formulation of selumetinib as the hydrogen sulphate salt (AZD6244 Hyd-
Sulfate), which will be used in this study. The maximum tolerated dose (MTD) for the 
suspension formulation was determined to be 100 mg twice daily, whereas for the capsule, the 
MTD was determined to be 75 mg twice daily. The emerging safety and tolerability profile of 
the capsule formulation is broadly consistent with that of the suspension formulation, although 
a higher frequency of fatigue and nausea has been reported with the capsule formulation 
compared to the suspension formulation in the phase II monotherapy studies. 
As of April 2012, over 1200 patients have received selumetinib as monotherapy or in 
combination with other anti-cancer agents in clinical studies (AstraZeneca and non 
AstraZeneca-sponsored studies, including investigator-sponsored studies). 
Two phase I studies (D1532C00005, D1532C00020) were performed with the Hyd-Sulfate 
formulation. Comparison of the frequencies from Study D1532C00005 and the AZ-sponsored 
phase II monotherapy studies described below, shows that there are higher percentages of 
patients reporting the most frequent AEs such as fatigue, dermatitis acneiform, diarrhoea, 
nausea and peripheral oedema with the Hyd-Sulfate formulation. This may be due to the 
higher plasma exposures achieved with the capsule formulation, but may also be in part as a 
consequence of the more heavily pre-treated patient population in study D1532C00005 having 
lower tolerances to developing toxicity. 
x
The frequencies of common AEs observed in Study D1532C00020 were generally 
more similar to that of Study D1532C00003 (free-base suspension formulation in a 
phase II population), which may mean that some of the differences in frequencies 
observed just reflect variations in the study population as the selumetinib safety 
profile is established. 
Two hundred and sixty nine (269) patients received selumetinib free base suspension 100 mg 
twice daily in 4 completed phase II monotherapy studies (D1532C00003, D1532C00008, 
D1532C00011, and D1532C00012). 
x
Rashes (including the preferred terms dermatitis acneiform, rash, rash 
maculopapular, rash macular, rash papular, acne, and folliculitis) were reported in 
approximately 70% of patients receiving treatment with selumetinib, and dermatitis 
acneiform was the most common AE term overall (54%).  Other commonly 
reported AEs were diarrhoea (49%), nausea (33%) and vomiting (24%).  Adverse 
events of peripheral oedema, periorbital oedema, and facial oedema were reported 
in 31%, 9%, and 4% of patients, respectively.  The AEs of fatigue or asthenia were 
reported in approximately 30% of patients in this phase II population.  Dyspnoea 
exertional or dyspnoea was reported in 13% of patients and, in individual studies, 
dyspnoea exertional was reported at a higher incidence in the selumetinib groups 
than in the comparator chemotherapy groups. 
x
Serious AEs were reported in 24% of patients receiving selumetinib monotherapy.  
The most frequently reported serious AEs were vomiting (1.5%), diarrhoea, 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
28(118) 
erysipelas, and pulmonary embolism (in 1.1% patients each).  Serious AEs of 
infections (bacterial sepsis, sepsis, infection, and bacterial arthritis) were reported in 
2.2% of patients. The most frequently related reported treatment-related SAE was 
vomiting (3 patients).  
x
In Study D1532C00003, small increases in blood pressure were observed after 1 
week on selumetinib, with mean increases of 7.4 mmHg (systolic, SBP) and 5.3 
mmHg (diastolic, DBP) at Week 8, compared with mean increases of 1.1 mmHg 
(SBP) and 0.5 mmHg (DBP) in the temozolomide comparator arm.  The AE of 
hypertension was reported in 18 patients (6.7%) receiving selumetinib in phase II 
monotherapy studies; 6 of these patients had hypertension at entry to the study, and 
a further 5 patients had documented risk factors for hypertension.  
x
Reversible asymptomatic reduction in left ventricular ejection fraction (LVEF) to 
below 55% has been reported in a small proportion of patients with advanced 
cancers in the monotherapy and randomised placebo controlled studies in 
combination with standard chemotherapies, with both formulations of selumetinib.  
In both placebo controlled studies no patient treated with selumetinib had severe 
LVEF impairment (< 35%) or symptomatic heart failure. Evidence of reversibility 
on continuing treatment with selumetinib has been demonstrated in some patients. 
LVEF scheduled assessments were only included in one phase II study 
(D1532C00003) and in the selumetinib group to evaluate a possible cardiac 
aetiology of the peripheral oedema reported in earlier studies. The median change in 
LVEF at Week 4 was 1.2 percentage points, and the individual change from 
baseline ranged from –20 to +19 percentage points. Adverse events of ejection 
fraction decreased, left ventricular dysfunction, or ventricular dysfunction were 
reported in a total of 5 patients (3.3%) receiving selumetinib (including 1 patient 
who had switched from temozolomide treatment after disease progression) versus 1 
patient (1%) in the comparator group.  
x
Review of clinical laboratory parameters in phase II monotherapy studies identified 
a trend toward increased alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) levels after starting treatment with selumetinib.  An 
increase in serum phosphate was observed in some patients after initiation of 
selumetinib, compared with patients randomised to comparator treatments.There 
was a trend toward a small mean decrease in albumin relative to the comparator.  
No other reports of selumetinib-related changes in laboratory parameters were 
considered to be of clinical relevance at this time.  There was no evidence of 
myelosuppression or renal impairment. 
x
Adverse events related to visual function have been reported across the programme 
with selumetinib.  Most often there were no specific clinical findings reported from 
patients that underwent ophthalmological evaluation after reporting the AE of visual 
disturbance.  AEs consistent with central serous retinopathy have been reported in a 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
29(118) 
small number of patients receiving treatment with selumetinib, generally in 
combination with other anti-cancer agents.  
x
There have been reports of pneumonitis-type events in a small number of patients 
receiving treatment with selumetinib. An association with selumetinib has not been 
established. An algorithm for investigation of dyspneoa is provided in Appendix G: 
"Guidance for Management of Adverse Events in Studies of Selumetinib." 
x
Weakness of neck extensor muscles in conjunction with creatine phosphokinase 
(CPK) increases (reversible on treatment interruption) have been reported in 3 out 
of 54 patients with uveal melanoma receiving selumetinib 75 mg twice daily in one 
non-AstraZeneca sponsored study. Increases in CPK levels have been recorded in a 
small number of patients receiving treatment with selumetinib. CPK elevations are 
present in some patients with muscle symptoms, although asymptomatic elevations 
have also been reported. A relationship between selumetinib and elevated CPK 
levels or myopathy has not been established. 
In the DTC pilot study described in Section 1.1.5.2 (Ho et al 2012), where 20 metastatic 
thyroid cancer patients were treated with a 4 week course of selumetinib 75 mg twice daily, all 
events attributed to selumetinib were Grade 1 or 2, and included fatigue (80%), maculo-
papular rash (70%), acneiform rash (25%), elevation in AST (70%; all Grade 1), elevation in 
ALT (45%; all Grade 1), diarrhea (45%), nausea (40%), limb edema (30%), oral mucositis 
(35%), constipation (20%), hypoalbuminemia (15%), decreased white blood cell count (15%), 
face edema (10%), scalp pain (10%), decreased platelet count (1 patient; Grade 1), eye 
disorder (1 patient; Grade 1 consisting of visual halos and slight blurriness that resolved after 
therapy stopped), hypertension (1 patient; Grade 1), periorbital edema (1 patient; Grade 1), 
and vomiting (1 patient, Grade 1).  One patient who was treated with RAI was subsequently 
diagnosed with myelodysplastic syndrome 51 weeks after RAI administration which 
subsequently evolved into acute leukaemia (this was determined to be unrelated to selumetinib 
and likely related to cumulative RAI toxicity as well as previous external beam radiation 
therapy).  All adverse events were readily managed with supportive mediations and were 
reversible upon discontinuation of selumetinib.  None of the 20 patients required dose delays 
or reductions due to selumetinib toxicity.   
In the only other study to specifically investigate selumetinib in differentiated thyroid cancer 
patients (the phase II study of 100 mg bid selumetinib, previous mix-and-drink formulation) in 
39 patients with RAI-refractory differentiated metastatic thyroid cancer (Hayes et al 2012). In 
these patients with RAI-refractory disease, common drug-related AEs included rash (77%), 
fatigue (49%), diarrhea (49%), and peripheral oedema (36%).  Grade 3 and 4 AEs were 
consistent with those across the selumetinib program and also included rash (18%), fatigue 
(8%), diarrhea (5%) and peripheral oedema (5%).  Twelve patients required dose reductions 
for reported AEs across the length of the study (the duration of treatment was greater than 16 
weeks for 69% of patients).  Six patients (15%) discontinued treatment due to adverse events. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
30(118) 
A study of selumetinib in combination with radiation in patients with non-small cell lung 
cancer has recently been opened but no safety or efficacy results are yet available from this 
study.  
Selumetinib is not mutagenic or clastogenic in vitro but produced increases in micronucleated 
immature erythrocytes in mouse bone marrow micronucleus studies.  Investigatory studies 
show that this is predominantly via an aneugenic mechanism which is consistent with 
disruption of normal spindle function as a consequence of the known pharmacological action 
of a MEK inhibitor.  With selumetinib Hyd-Sulfate, a NOEL of 24 mg/kg/day (for 2 days) 
was established for induction of micronuclei, with plasma exposures significantly above those 
observed in cancer patients at the maximum tolerated dose of 75 mg twice daily.  This 
suggests that selumetinib will have little potential to cause aneugenicity in dividing cell 
populations in patients at the proposed clinical dose.  Thus, any additional aueugenic risk from 
a 5 week course (maximum 43 days) of twice daily 75 mg selumetinib dosing in this 
potentially curative patient setting, is considered to be negligible in comparison with the 
known and more substantial risk from radiation exposure following a therapeutic dose of 131I 
(100 mCi) that patients will receive as part of standard of care.    
In summary, selumetinib has been shown to have an acceptable profile of side effects, in an 
extensive safety database for a compound at this stage of development.   
Further details regarding the safety profile of selumetinib can be found in the Investigator 
Brochure. 
1.2 
Research hypothesis 
Pre-treatment with selumetinib enhances the uptake of radioactive iodine in differentiated 
thyroid cancer, resulting in a greater incidence of complete remission after adjuvant RAI 
therapy in patients at high risk of primary treatment failure. 
1.3 
Rationale for conducting this study 
Unfortunately a significant proportion of thyroid cancer patients are not cured by their initial 
surgery and RAI therapy. This is often due to the inability of their cancer cells to adequately 
incorporate RAI (due to reduced expression of NIS). In such cases, repeated administration of 
RAI may be given (for RAI avid disease) with the aim of inducing remission and curing their 
disease. This outcome however is not guaranteed, and patients who subsequently develop 
refractory metastatic disease have a much poorer prognosis and may eventually succumb to 
their disease; at least one third of patients who develop metastatic disease have no or very low 
uptake and are thus not amenable to further RAI treatment.  There is thus an urgent need for a 
medicine that can enhance the effectiveness of initial RAI treatment and increase the 
probability of achieving remission, thereby preventing more patients from developing distant 
metastatic disease.  


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
31(118) 
1.4 
Benefit/risk and ethical assessment 
It is clear from the Investigator-sponsored study (Ho et al 2012), that a short course of 
selumetinib prior to RAI therapy, is effective in enhancing RAI uptake, reducing tumour 
marker (Tg) levels, and reducing tumour size in heavily pre-treated patients with documented 
RAI-refractory disease. Most patients in the pilot clinical study had numerous metastatic 
lesions, some of which were refractory to RAI at baseline and some of which were partially 
RAI avid at baseline.  Importantly, selumetinib pre-treatment not only restored RAI uptake in 
previously refractory lesions, but also increased RAI uptake in the majority of partially avid 
lesions (typically by more than 100% compared to the baseline value; 3- to 7-fold increases in 
maximum SUVs in such lesions were consistently observed). This pilot data not only supports 
the preclinical hypothesis that inhibiting the MAPK pathway can convert non-RAI avid 
lesions to RAI avid tumours, but also demonstrates that iodine uptake in previously iodine 
sensitive lesions can be significantly increased with selumetinib.  This observation broadens 
the potential clinical applicability of this approach beyond just RAI-refractory thyroid cancer, 
to the use of selumetinib and RAI as part of upfront adjuvant treatment of RAI-naïve and 
susceptible DTC.  
The potential benefit to patients in this study is therefore high, with an increased chance of 
complete remission. The toxicity risk from a short course (approximately 5 weeks) of 
selumetinib treatment has been carefully considered for this potentially curative population; 
the side effect profile of selumetinib in the short timeframe (maximum 6 weeks of exposure) 
is considered to be predictable, manageable and reversible (mainly rash and fatigue). The long 
term risk of secondary malignancies associated with RAI is considered low from a single 
100 mCi dose, as these are rare and more typically develop following cumulative RAI 
treatments and exposure. Patients under the age of 18 years will be excluded to minimise any 
risk of increased radioactivity exposure in a younger population. The side effect profile of 
both selumetinib and RAI will be monitored over the entire 3 year study duration for each 
patient. 
2. 
STUDY OBJECTIVES 
2.1 
Primary objectives 
x
To compare the efficacy of selumetinib with radioactive iodine therapy (RAI), 
versus placebo with RAI, by assessment of complete remission rate at 18 months 
post RAI treatment in the overall study population. Complete remission is defined 
in Section 6.4.1. 
x
To compare the efficacy of selumetinib with RAI, versus placebo with RAI, by 
assessment of complete remission rate at 18 months post RAI treatment in a sub-
group of patients with tumours known to be mutation positive for BRAF or NRAS 
(defined in Section 6.10.1). Complete remission is defined in Section 6.4.1. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
32(118) 
2.2 
Secondary objectives 
1. 
To compare the efficacy of selumetinib with RAI, versus placebo with RAI by 
assessment of clinical remission rate at 18 months post RAI treatment in the overall 
study population. Clinical remission is defined in Section 6.4.6. 
2. 
To compare the efficacy of selumetinib with RAI, versus placebo with RAI by 
assessment of clinical remission rate at 18 months post RAI treatment in a sub-group 
of patients with tumours known to be mutation positive for BRAF or NRAS (defined in 
Section 6.10.1). Clinical remission is defined in Section 6.4.6. 
3. 
To assess the safety and tolerability of selumetinib with RAI compared to placebo with 
RAI. 
4. 
To investigate the pharmacokinetics (PK) of selumetinib and N-desmethyl selumetinib 
when administered to patients with differentiated thyroid cancer. 
2.3 
Exploratory objectives 
1. 
To explore subsequent thyroid cancer therapy given to patients who receive  
selumetinib with RAI, or placebo with RAI. 
2. 
To investigate the relationship between selumetinib and/or N-desmethyl selumetinib 
plasma concentrations/exposure and clinical outcomes, efficacy, AEs and/or safety 
parameters. 
3. 
To collect tumour, plasma and serum samples for potential future research on 
biomarkers relevant to DTC and response and resistance to study treatments.  
4. 
To collect and store DNA for future exploratory research into genes/genetic variation 
that may influence response (ie, distribution, safety, tolerability and efficacy) to 
selumetinib or RAI and/or susceptibility to cancer. 
The exploratory analysis will be reported separately from the CSR. 
3. 
STUDY PLAN AND PROCEDURES 
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
standard procedures. 
3.1 
Overall study design and flow chart 
This is a double-blind, randomised, placebo-controlled study to assess the efficacy and safety 
of a short course (approximately 5 weeks) of selumetinib (75 mg, orally twice daily) in 
combination with adjuvant RAI therapy compared to placebo and adjuvant RAI therapy, in 
patients with differentiated thyroid cancer at high risk of primary treatment failure. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
33(118) 
Approximately 228 patients will be randomised 2:1 selumetinib to placebo. 
This will be a multi-centre, international study; it is anticipated that approximately 50 centres 
will recruit patients in South and/or North America and Europe.  
3.1.1 
Treatment Plan 
Following randomisation, patients will take their assigned study treatment (selumetinib or 
placebo) for a period of approximately 5 weeks, twice daily.  Study treatment will begin 
approximately 4 weeks prior to the planned day of RAI therapy. Refer to Table 2 for an 
example study treatment plan. The following treatment criteria must be adhered to: 
1. 
Day 1 of study treatment must occur: 

no earlier than 6 weeks after the patient’s thyroid cancer surgery (their 
last surgery if it was a 2-stage thyroidectomy), and   

no later than 16 weeks after the patient’s thyroid cancer surgery (their last 
surgery if it was a 2-stage thyroidectomy).   
2. 
It is essential that patients remain on study treatment continuously for a minimum 
of 7 consecutive days prior to their planned RAI therapy, on the day of RAI 
therapy, and for 5 consecutive days afterwards.  If necessary, RAI therapy may be 
rescheduled at the discretion of the Investigator until the patient has been on study 
treatment for a minimum of 7 consecutive days beforehand.   
3. 
Study treatment with selumetinib or placebo will typically last for 36 days, but must 
be for no longer than 43 days (this allows the planned RAI to be postponed by up to 
1 week if absolutely necessary).   
4. 
Patients will be required to adhere to a low iodine diet for a period of 1 week before 
their planned RAI adjuvant treatment, until the day after their RAI treatment. Refer 
to Section 5.1.1 and the example diet in Appendix F for further details. 
5. 
For each of the 2 days immediately prior to their planned RAI therapy, patients will 
receive a recombinant human TSH injection (rhTSH, Thyrogen), in order to 
stimulate iodine uptake (refer to Section 5.5.4 for details). 
6. 
Following the 2 days of rhTSH injections, patients will receive their planned RAI 
therapy the immediate next day (refer to Section 5.5.4 for further RAI dosing 
information).   
7. 
Twice daily dosing of selumetinib/placebo will continue for 5 days following RAI 
therapy (Day 36 will typically be the last day of study treatment, but this can extend 
to Day 43 if necessary). 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
34(118) 
Table 2 
Example study treatment plan  
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Sunday 
Day 1 
X 
Day 2 
X 
Day3 
X 
Day 4 
X 
Day 5 
X 
Day 6 
X 
Day 7 
X 
Day 8 
X 
Day 9 
X 
Day 10 
X 
Day 11 
X 
Day 12 
X 
Day 13 
X 
Day 14 
X 
Day 15 
X 
Day 16 
X 
Day 17 
X 
Day 18 
X 
Day 19 
X 
Day 20 
X 
Day 21 
X 
Day 22 
X 
Day 23 
X 
Day 24 
X 
Low I diet 
Day 25 
X 
Low I diet 
Day 26 
X 
Low I diet 
Day 27 
X 
Low I diet 
Day 28 
X 
Low I diet 
Day 29 
X 
Low I diet 
Thyrogen 
Day 30 
X 
Low I diet 
Thyrogen 
Day 31 
X 
Low I diet 
RAI 
Day 32 
X 
Low I diet 
Day 33 
X 
Day 34 
X 
Day 35 
X 
Day 36 
X  
last day of 
study 
treatment 
 
Day 38  
(Day 36-41) 
WBS scan 
 (3-10 days 
after RAI 
dose) 
 
 
 
 
 X: Study treatment administration (selumetinib or placebo, twice daily) 
RAI: radioactive iodine therapy (131I) refer to Section 5.5.4.2 for details 
This suggested treatment plan is an example only. The treatments may be planned for different days as long as all 
criteria in Section 3.1.1 are met. 
 
3.1.2 
Follow-up plan 
Following completion of RAI therapy and planned discontinuation of study treatment 
(randomised selumetinib or placebo); patients will be followed up as follows: 
1. 
3-10 days after RAI therapy, patients will undergo a post-therapy whole body RAI 
(131I) nuclear medicine scan to determine where the RAI has localized in the body 
(refer to Section 6.4.4.2 for further detail). 
2. 
Patients will be monitored for TSH and thyroxine (T4) levels as per local standard 
of care (refer to Section 6.4.3.3 for further detail). Note that T4 levels will not be 
collected in the study database. 
3. 
At 9 months (±3 months) following RAI treatment, patients will be assessed for: 
(a) 
TSH-suppressed Tg and Tg antibody levels (TgAb).  Refer to Section 5.9.1.1 
for further details. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
35(118) 
(b) 
Neck ultrasound (US). Refer to Section 5.9.1.2 for further details. 
It is important that these assessments are not performed earlier than 6 months after 
RAI treatment.  
4. 
Patients will be assessed for their complete remission status at the primary endpoint 
18 months following their RAI treatment.  A staged approach to the primary 
endpoint assessments will be used in this study in order to determine remission 
status (presence or absence of thyroid cancer), such that each patient may not 
require all assessments. Refer to Section 6.4, Table 4 and Figure 3 for further 
details. The primary endpoint assessments must be started 18 months ± 2 weeks 
following the patient’s RAI dose, and all necessary primary endpoint assessments 
must be completed within an 8 week period. 
Further thyroid cancer therapy (eg, additional surgery, RAI re-treatment, external 
beam radiotherapy or systemic therapy) should only be given during the initial 
18 month follow-up period according to the re-treatment criteria in Section 5.9. Any 
patient that is re-treated in the 18 month period following their RAI therapy will not 
require any primary endpoint assessments performing (they will be determined not 
to be in complete remission for the purpose of the study and will enter standard of 
care follow up, remaining in the study until the 3 year follow up). 
5. 
Following the primary endpoint assessments (or re-treatment), all randomised 
patients will be further followed-up at 3 years following their RAI treatment.  It is 
the responsibility of the study investigator to ensure they conduct follow-up as 
described in this protocol if patients transfer to non-study hospitals, or if patients are 
discharged for routine follow up at other institutions (eg, family doctor or local non-
specialist hospital). 
Assessments planned at each visit are detailed in Table 3, Table 4 and Section 6. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
36(118) 
Figure 1 
Study flow chart  
 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
37(118) 
Table 3 
Study Plan 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Visit Description 
Screening 
Randomi
sation 
On -
treatment 
safety 
visit 
Thyrogen 
RAI 
therapy 
Last day 
of 
treatment 
30 days 
post 
treatment 
4 Month 
safety 
follow up 
9 
Month 
FU 
Primary 
endpoint 
assessmentsa 
27 
Month 
safety 
follow up 
3 Year 
FU 
Protocol 
Section 
Timing 
Day  
-28 to –1 
Day 1 
Day 14 
Days  
29 & 30 
Day 31 
 Day 36 
Week 10 
4 months 
post visit 
5 
9 
months 
post 
visit 5 
18 months 
post visit 5 
27 
months 
post visit 
5 
3 years 
post 
visit 5 
 
Visit Window 
N/A 
N/A 
±1wk 
N/A 
N/A 
N/A 
± 2 days 
± 2 
weeks 
± 3 
months 
Refer to 
Table 4 
± 2 
months 
± 1 
month 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
X 
X 
(Day 29 
or 30) 
 
 
X 
 
 
 
 
 
6.5.6 
Additional screening 
procedures  
X 
 
 
 
 
 
 
 
 
 
 
 
6.2 
Provision of archival 
tumourb 
 
X 
 
 
 
 
 
 
 
 
 
 
6.10.1.
1 
Plasma/serum sample for 
exploratory analysisb 
 
X (pre-
dose) 
 
 
 
 
 
 
 
 
 
 
6.10.2 
Pregnancy test 
X 
 
 
 
X 
 
 
 
 
Xa 
 
 
6.5.9.1 
Optional genetic consent & 
sample (whole blood)  
 
X (pre-
dose) 
 
 
 
 
 
 
 
 
 
 
6.9 
Adverse eventsc 
X 
 
 
 
 
 
 
 
 
 
 
 
6.5.3 
Concomitant medications 
X 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Telephone follow up for 
safetyd 
 
 
 
 
 
 
 
X 
 
 
X 
 
6.5.3 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
38(118) 
Table 3 
Study Plan 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Visit Description 
Screening 
Randomi
sation 
On -
treatment 
safety 
visit 
Thyrogen 
RAI 
therapy 
Last day 
of 
treatment 
30 days 
post 
treatment 
4 Month 
safety 
follow up 
9 
Month 
FU 
Primary 
endpoint 
assessmentsa 
27 
Month 
safety 
follow up 
3 Year 
FU 
Protocol 
Section 
Timing 
Day  
-28 to –1 
Day 1 
Day 14 
Days  
29 & 30 
Day 31 
 Day 36 
Week 10 
4 months 
post visit 
5 
9 
months 
post 
visit 5 
18 months 
post visit 5 
27 
months 
post visit 
5 
3 years 
post 
visit 5 
 
Visit Window 
N/A 
N/A 
±1wk 
N/A 
N/A 
N/A 
± 2 days 
± 2 
weeks 
± 3 
months 
Refer to 
Table 4 
± 2 
months 
± 1 
month 
 
Vital signs (including height 
at screening), weight 
X 
X (pre-
dose) 
X 
X 
(Day 29 
or 30) 
 
 
X 
 
 
 
 
 
6.5.8 
Clinical chemistry 
X 
X (pre-
dose) 
X 
X 
(Day 29 
or 30) 
 
 
X 
 
 
 
 
 
6.5.5 
Haematology 
X 
X (pre-
dose) 
X 
X 
(Day 29 
or 30) 
 
 
X 
 
 
X 
 
X 
6.5.5 
Urinalysis  
X 
 
X 
 
 
 
X 
 
 
 
 
 
6.5.5 
ECGe 
X 
X 
 
Xe (Day 
29 or 30) 
 
 
X 
 
 
 
 
 
6.5.7.2 
ECHO/MUGAf 
X 
 
 
 
 
 
X 
 
 
 
 
 
6.5.7.1 
Ophthalmologic 
examinationf 
X 
 
 
 
 
 
X 
 
 
 
 
 
6.5.9.2 
Selumetinib/placebo dosingg 
 twice daily 
 
 
 
 
 
 
 
 
 
 
 
 
5.5.2 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
39(118) 
Table 3 
Study Plan 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Visit Description 
Screening 
Randomi
sation 
On -
treatment 
safety 
visit 
Thyrogen 
RAI 
therapy 
Last day 
of 
treatment 
30 days 
post 
treatment 
4 Month 
safety 
follow up 
9 
Month 
FU 
Primary 
endpoint 
assessmentsa 
27 
Month 
safety 
follow up 
3 Year 
FU 
Protocol 
Section 
Timing 
Day  
-28 to –1 
Day 1 
Day 14 
Days  
29 & 30 
Day 31 
 Day 36 
Week 10 
4 months 
post visit 
5 
9 
months 
post 
visit 5 
18 months 
post visit 5 
27 
months 
post visit 
5 
3 years 
post 
visit 5 
 
Visit Window 
N/A 
N/A 
±1wk 
N/A 
N/A 
N/A 
± 2 days 
± 2 
weeks 
± 3 
months 
Refer to 
Table 4 
± 2 
months 
± 1 
month 
 
PK blood samplesh 
 
X 
 
Xh (Day 
29 or 30) 
 
 
 
 
 
 
 
 
6.7 
Low iodine dieti 
 
 
 
X 
X 
 
 
 
 
Xa 
 
 
5.1.1 
Thyrogen injection 
 
 
 
Xx2 
(Day 29 
and 30) 
 
 
 
 
 
Xx2a 
 
 
5.5.4.1 
131I (RAI) treatment  
single 100 mCi dose 
 
 
 
 
X 
 
 
 
 
 
 
 
5.5.4.2 
131I 5 diagnostic dose for 
WBS 
single 5 mCi dose 
 
 
 
 
 
 
 
 
 
Xa 
 
 
5.5.4.2 
131I nuclear medicine WBS 
scan 
 
 
 
 
 
Xj 
 
 
 
Xa 
 
 
6.4.4.2 
Re-treatment assessmentk 
 
 
 
 
 
 
 
 
X 
X 
 
X 
5.9 
Blood sample for TSH  
 
 
 
 
 
 
 
 
X 
X  
 
 
6.4.3.3 
Blood sample for 
suppressed Tg 
 
 
 
 
 
 
 
 
Xn 
X 
 
 
6.4.3.1 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
40(118) 
Table 3 
Study Plan 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Visit Description 
Screening 
Randomi
sation 
On -
treatment 
safety 
visit 
Thyrogen 
RAI 
therapy 
Last day 
of 
treatment 
30 days 
post 
treatment 
4 Month 
safety 
follow up 
9 
Month 
FU 
Primary 
endpoint 
assessmentsa 
27 
Month 
safety 
follow up 
3 Year 
FU 
Protocol 
Section 
Timing 
Day  
-28 to –1 
Day 1 
Day 14 
Days  
29 & 30 
Day 31 
 Day 36 
Week 10 
4 months 
post visit 
5 
9 
months 
post 
visit 5 
18 months 
post visit 5 
27 
months 
post visit 
5 
3 years 
post 
visit 5 
 
Visit Window 
N/A 
N/A 
±1wk 
N/A 
N/A 
N/A 
± 2 days 
± 2 
weeks 
± 3 
months 
Refer to 
Table 4 
± 2 
months 
± 1 
month 
 
Blood sample for TgAb 
X 
 
 
 
 
 
 
 
X 
X 
 
 
6.4.3.4 
Blood sample for rhTSH-
stimulated Tg 
 
 
 
 
 
 
 
 
 
Xa 
 
 
6.4.3.2 
Neck ultrasound 
Xl 
 
 
 
 
 
 
 
X 
X 
 
 
6.4.4.1 
Neck MRI 
Xl 
 
 
 
 
 
 
 
 
Xa 
 
 
6.4.4.3 
Chest CT without contrast  
Xl 
 
 
 
 
 
 
 
 
Xa 
 
 
6.4.4.4 
Final follow-up assessment 
of clinical status 
 
 
 
 
 
 
 
 
 
 
 
X 
6.4.8 
Biopsy/FNA for disease 
confirmation 
 
 
 
 
 
 
 
 
Xm 
Xm 
 
 
6.4.4.5 
Tumour biopsy on 
progression (optional) 
Optional sample on disease progression (for example, if the patient is re-treated for persistent or recurrent thyroid cancer, or has further surgery). 
Note that both a plasma and serum sample for exploratory analysis should also be taken on disease progression. 
6.10.3 
6.10.2 
Study Plan Table 3 Footnotes 
a Refer to Table 4 and Section 6.4.2. 
b  Provision of these samples is mandatory in this study. Samples should also be obtained on progression (refer to Section 6.10.2). 
c All AEs/SAEs should be collected from the day of consent until 30 days following the last dose of study treatment. From then on, all SAEs (regardless of 
causality), and all AEs related to either RAI, or the combination of RAI and study treatment, should be collected until the last study visit 3 years 
following the patient’s RAI dose. The same AE collection scheme applies for any re-treated patient.  


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
41(118) 
d The Investigator (or delegate) is required to contact the patient by telephone to follow up for any safety information (according to the collection scheme 
detailed in Section 6.5). For re-treated patients, safety follow-up should continue according to the protocol-scheduled visits, but may be collected by 
telephone if necessary at each visit (refer to Section 5.9). 
e Single ECG assessments 1-2 hours following the first dose on Day 1 and Day 29 or Day 30 of study treatment. A single ECG assessment is also required 
whenever an ECHO/MUGA is performed, on any cardiorespiratory AE, and for premature discontinuation. 
f These assessments must also be performed on symptomatology according to the relevant protocol section. 
g Study treatment must be initiated no earlier than 6 weeks after the patient’s thyroid cancer surgery, and no later than 16 weeks after the patient’s thyroid 
cancer surgery (their last surgery if it was a 2-stage thyroidectomy). 
h Each patient will be asked to contribute 8 PK blood samples, one from each of the four pre defined time windows on both Day 1 and Day 29 or Day 30.  The 
Day 29 or Day 30 PK blood samples may be taken earlier, from Day 22 onwards of study treatment if preferred, but it is essential that all PK blood 
samples are collected before the RAI dose is administered. (a) Pre-dose (within 15 minutes of dosing), (b) between 15 minutes and 1 hour post-dose, (c) 
between 1.5 and 2.5 hours post-dose, and (d) between 3 and 8 hours post-dose. 
i  All patients must adhere to a low iodine diet (an example diet is provided in Appendix F). 
j The post-RAI WBS may be performed any time from 3-10 days following the patient’s RAI dose (thus it does not have to be on the same day as the last dose 
of study treatment). 
k The re-treatment assessment will establish whether the patient has received any further treatment for thyroid cancer. Refer to Section 5.9 for the study 
criteria for re-treatment in the initial 18 months following the patient’s RAI dose. 
l The post-operative imaging assessments must be performed no sooner than 4 weeks post-surgery, and after all other screening assessments have been 
performed (ie, they should not be performed for any patient that is otherwise ineligible).  
m Only if required (refer to Section 6.4.4.5) 
n A repeat sample for suppressed Tg may be required 2-4 weeks later, refer to Section 5.9.1.1. 
For imaging data that is required to be sent to the central imaging CRO at any point in the study refer to Section 6.4.4.5. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
42(118) 
Table 4 
Study Plan for the 18 month Primary Endpoint Assessments 
A staged approach to the primary endpoint assessments will be used in this study in order to determine remission status (absence of 
thyroid cancer), such that each patient may not require all assessments. Full details are outlined in Section 6.4.2. 
 
Stage 1 
Stage 2 
Stage 3 
Protocol Section 
Time window 
Stage 1 assessments must be started 18 months ± 2 weeks following the patient’s RAI 
dose, and all necessary primary endpoint assessments must be completed within an 8 
week period. 
6.4.2 
Thyroid cancer re-treatment assessmenta 
Xa 
 
 
5.9 
Suppressed Tg  
X 
 
 
6.4.3.1 
TSH 
X 
 
 
6.4.3.3 
TgAbb 
Xb 
Xb 
 
6.4.3.4 
Neck USf 
X 
 
 
6.4.4.1 
Biopsy or FNAd 
Xd 
 
 
6.4.4.5 
Haematology 
X 
 
 
6.5.5 
Low iodine diete 
 
Xe 
 
5.1.1 
Thyrogen injectionc 
 
X x 2c 
 
5.5.4.1 
Stimulated Tgc 
 
Xc 
 
6.4.3.2 
Pregnancy test 
 
X 
 
6.5.9.1 
Diagnostic 5mCi 131I dosec 
 
Xc 
 
5.5.4.2 
WBS (nuclear medicine scan)c, f 
 
Xc 
 
6.4.4.2 
Neck MRI with contrastf 
 
 
X 
6.4.4.3 
Chest CT without contrastf 
 
 
X 
6.4.4.4 
Selumetinib/RAI-related AE/SAEs  
 
 
 
6.5.3 
 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
43(118) 
Footnotes for Table 4: Study Plan for the 18 month Primary Endpoint Assessments 
a Patients that have been re-treated for thyroid cancer between their initial RAI dose and the primary endpoint assessments 18 months later (refer to Section 
5.9 for re-treatment criteria), will not have any primary endpoint assessments performed, they will remain in the study and enter standard of care follow 
up according to local practice. They should still be followed up for safety information at 18 m, 27 m and 3 years following their initial RAI dose. 
b For decision making purposes at any time in the study, standardised central analysis results must be used. If the stage 1 blood sample is positive for TgAb, 
but the stage 2 blood sample is negative for TgAb, then a third blood sample 10 days later (± 3 days) is required to confirm absence of TgAb.  
c Patients will receive 2 Thyrogen injections on consecutive days (day 1 and 2), followed by a diagnostic dose (5mCi) of 131I on either day 2 or day 3, and a 
blood draw for stimulated Tg central assessment and WBS both on day 5.  
d Only if required to prove absence of disease for suspicious lesions (refer to Section 6.4.4.5). 
e Patients will be required to adhere to a low iodine diet for a period of 1 week before their planned RAI adjuvant treatment, until the day after their RAI 
treatment. Refer to Section 5.1.1 and the example diet in Appendix F for further details. 
f For imaging data that is required to be sent to the central imaging CRO refer to Section 6.4.4.5.


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
44(118) 
3.2 
Rationale for study design, doses and control group 
This study is designed to determine the efficacy of a 5-week course of selumetinib or placebo, 
and adjuvant RAI therapy, by assessing the rate of complete remission at 18 months post-RAI 
therapy.  
The dose and duration of selumetinib treatment in this study (75 mg twice daily for 5 weeks) 
is selected to be consistent with the pilot study, which has previously demonstrated enhanced 
RAI uptake following selumetinib treatment, reduction in Tg levels, and reduced tumour size 
following RAI therapy, in patients with RAI-refractory metastatic thyroid cancer (Ho et al 
2012).  In addition to the effects of selumetinib on the sodium iodine transporter (refer to 
Section 1.1.5.1), selumetinib may also increase levels of thyroid peroxidase and thyroglobulin 
in any remaining thyroid cells. These proteins are required to organify and retain iodide in 
thyroid cells, thus facilitating greater retention of 131I, and a higher dose of radiation to cancer 
cells. For this reason, patients will remain on selumetinib treatment for 5 days after receiving 
the therapeutic dose of RAI. 
Since RAI is the standard of care for this patient population, the selumetinib/RAI treatment 
group will be compared to a placebo/RAI control group for all study endpoints. 
The population who will participate in this study will be patients with differentiated thyroid 
cancer at high risk of primary treatment failure that would routinely require RAI adjuvant 
therapy as standard of care. This risk-stratified population has been selected because it is 
known that they are at an increased risk of failing to achieve remission following standard 
initial therapy, and therefore require more effective treatment strategies (refer to Section 
1.1.3). This study is intended to be an adjuvant therapy trial for patients without known 
structural persistent disease; patients with known distant metastases at screening will be 
excluded in order to minimise heterogeneity of the efficacy recorded.  
The second primary efficacy endpoint will be assessed in patients with tumours carrying 
BRAF or NRAS mutations, as these are known to constitutively activate the MEK signalling 
pathway. Treatment with a MEK inhibitor may thus be hypothesised to deliver a greater 
treatment effect in these patients. However, the pathway can be activated in many ways such 
that these patients are not likely to be the only population to benefit. Incorporation of a 
genetically predefined study population enables this hypothesis to be examined (mutation 
analysis of samples to identify the genetically predefined study population will be performed 
post-randomisation, and prior to data base lock for the primary endpoint data analysis). 
Enhancing RAI uptake into thyroid cancer cells has the potential to increase the incidence of 
complete remission following RAI treatment. It has been shown that the incidence of 
complete remission following initial RAI treatment correlates with long-term outcome, and if 
complete remission has not been achieved, further treatment is frequently administered 
(Castagna et al 2011, Tuttle et al 2010).    
A study has retrospectively evaluated the time to nadir Tg in 299 patients who did not receive 
additional therapy after total thyroidectomy and RAI (Padovani et al 2012).  This patient 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
45(118) 
population includes both patients with no evidence of disease (remission) and patients with 
low level disease who are being observed (median follow up time is 7 years).  Figure 2 
illustrates that 94% of the 223 patients with no evidence of disease achieved a suppressed Tg 
level of < 1 ng/mL (the biochemical component of remission) by 18 months after initial RAI 
therapy. Therefore, it is expected that most patients who are likely to achieve remission in 
both arms will have done so by this time (for the purpose of this study both biochemical and 
structural absence of disease will be assessed).  Longer follow-up would not be expected to 
change the conclusions regarding an efficacy difference between the two study arms. In 
patients with similar characteristics to those planned in this study, a similar pattern and extent 
of Tg decline is also seen (Tuttle RM, unpublished sub-analysis of data from Padovani et al 
2012).  Previous studies have used time-points ranging from 8 to 24 months to assess 
remission rates after primary treatment of surgery and RAI (Castagna et al 2011, Tuttle et al 
2010, Vaisman et al 2012).   
Taking all the data into consideration, the incidence of complete remission at 18 months 
following initial RAI therapy has been selected as the primary endpoint for the proposed 
study.  Each randomised patient will be followed beyond their 18 month primary endpoint 
assessment, until 3 years after their RAI treatment, in order to further assess both the clinical 
status of patients, and the safety profile of selumetinib and RAI beyond the primary analysis 
(refer to Section 6.4.8).   
Figure 2 
Time course to achieving a suppressed Tg<1 ng/mL in patients 
receiving total thyroidectomy and RAI therapy 
 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
46(118) 
4. 
PATIENT SELECTION CRITERIA 
Investigator(s) should keep a record, (eg, patient screening log), of patients who entered pre-
study screening.  
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule. 
4.1 
Inclusion criteria 
For inclusion in the study patients should fulfil the following criteria: 
1. 
Provision of informed consent prior to any study specific procedures. The main 
study consent will include mandatory consent to provide a sample of archival 
tumour material.  
2. 
Males and females aged 18 years or above. 
3. 
Patients with histologically or cytologically confirmed follicular cell derived 
differentiated thyroid cancer including papillary thyroid cancer and all variants, 
follicular thyroid cancer and all variants, and poorly differentiated thyroid cancer.  
4. 
Note: Patients with a diagnosis of Hürthle cell carcinoma should be excluded. These 
are defined as having an invasive tumour composed of >75% of oncocytic (Hürthle) 
cells lacking the nuclear features of papillary carcinoma, tumor necrosis and marked 
mitotic activity. Patients with oncocytic (Hürthle cell variants) of papillary thyroid 
carcinoma defined as a tumour composed of a majority of oncocytic (Hürthle) cells 
having the nuclear features of papillary carcinoma are eligible to participate. 
5. 
Patients presenting with any one of the following staging categories post-surgery: 
(a) 
Primary tumour greater than 4 cm  
(b) 
Primary tumour of any size with gross extrathyroidal extension outside the 
thyroid gland (T4 disease) 
(c) 
N1a or N1b disease with at least 1 lymph node  1 cm 
(d) 
N1a or N1b disease involving 5 or more lymph nodes (of any size) 
Note: Patients with known metastatic disease at screening will be ineligible for this 
study as per the exclusion criteria. 
6. 
Patients must have had a one or two-stage total thyroidectomy with therapeutic neck 
dissection of any clinically apparent metastatic lymph nodes (levels I to VII of the 
lateral and central neck). All known tumour must have been resected.  


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
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Note, the optimal surgical procedure is based on the findings from preoperative 
ultrasound, to identify the extent of lymph node metastases and thereby facilitate 
compartment-oriented neck dissection for complete surgical removal of all gross 
disease. Prophylactic neck dissection is not required or encouraged, but may be 
performed at the discretion of the treating surgeon. As the surgical procedure(s) will 
have been performed before study consent, any patient for whom a total 
thyroidectomy cannot be verified must be excluded from the study (note that 
patients having undergone a robotic or endoscopic thyroidectomy, or any other 
novel or remote access surgical technique must also be excluded). For patients who 
have had a two-stage thyroidectomy, the second surgical procedure must have taken 
place no later than 12 weeks after the first procedure, otherwise the patient is not 
eligible. 
7. 
Patients must have all of the following post-operative assessments performed no 
sooner than 4 weeks post-surgery (post their last surgery if it was a 2-stage 
thyroidectomy) and the results from each must verify the absence of macroscopic 
disease: 
(a) 
Neck US exam  
(b) 
Neck MRI with contrast 
(c) 
Chest CT without contrast 
Refer to Section 6.3 for further details. These assessments must be performed within 
the 28 day screening period (but ideally after all other screening assessments have 
been performed, ie, they should not be performed for any patient that is otherwise 
ineligible). 
8. 
Patients must be suitable for radioactive iodine therapy. 
9. 
Patients must be suitable for TSH suppression with a goal of 0.5 mIU/L TSH for 
the duration of the study (this may exclude some patients with cardiac conditions or 
osteoporosis). 
10. 
Patients must be willing and able to start study treatment within 16 weeks of their 
thyroid cancer surgery (their last surgery if it was a 2-stage thyroidectomy). Note 
that study treatment must not be initiated within 6 weeks of the patient’s last 
surgery. 
11. 
WHO or ECOG Performance Status 0 or 1. 
12. 
Females must: 
(a) 
be using adequate contraceptive measures (refer to Section 5.1.2),   


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
48(118) 
(b) 
not be breast feeding (breast feeding must be discontinued in order to 
participate in this study), 
(c) 
have a negative pregnancy test prior to the start of dosing if they are of child-
bearing potential, 
(d) 
or must have evidence of non-child-bearing potential by fulfilling one of the 
following criteria at screening: 
(i) 
Post-menopausal defined as aged more than 50 years and amenorrhoeic 
for at least 12 months following cessation of all exogenous hormonal 
treatments. 
(ii) Women under 50 years old will be considered postmenopausal if they 
have been amenorrheic for at least 12 months following cessation of 
exogenous hormonal treatments, and with LH and FSH levels in the post-
menopausal range for the institution. 
(iii) Documentation of irreversible surgical sterilisation by hysterectomy 
and/orbilateral oophorectomy and/or bilateral salpingectomy but not tubal 
ligation. 
13. 
Male patients with sexual partners who are pregnant or who could become pregnant 
(ie, women of child-bearing potential) must agree to use acceptable methods of 
contraception until 12 weeks after completing study therapy, or longer if required 
for standard RAI administration restrictions and in accordance with local labels, to 
avoid pregnancy and/or potential adverse effects. 
14. 
Adequate organ function as defined by: 
(a) 
ANC  1.5x109/L (1500 per mm3) 
(b) 
Platelets  100 x 109/L (100,000 per mm3) 
(c) 
Hemoglobin  9 g/dL 
(d) 
ALT/SGOT and AST/SGPT < 2.5 X upper limit of normal (ULN). 
(e) 
Bilirubin  1.5 X ULN (with the exception that patients with elevated 
unconjugated bilirubin due to a pre-existing diagnosis of Gilbert’s syndrome 
are eligible for the study) 
(f) 
Serum creatinine clearance > 50mL/min by either Cockcroft-Gault formula 
(see Appendix E) or 24hr urine collection analysis. 
15. 
Patients must be able to swallow selumetinib/placebo capsules for the duration of 
the study treatment period. This may exclude some patients with swallowing 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
49(118) 
dysfunction due to the specific technique required for their thyroid surgery. 
Functional assessment of swallowing ability may be made by the treating 
Investigator. 
4.1.1 
Genetics research study (optional blood sample) 
1. 
For inclusion in the optional genetics research study patients must provide optional 
genetics research informed consent. 
2. 
If a patient declines to participate in the genetics research, there will be no penalty 
or loss of benefit to the patient.  A patient who declines genetics research 
participation will not be excluded from any other aspect of the main study. 
4.1.2 
Biomarkers research study on tumour progression biopsy 
For inclusion in the optional progression tumour sample study, patients must provide optional 
consent for this sample to be obtained. 
If a patient declines to provide consent to obtain optional tumour sample on progression, there 
will be no penalty or loss of benefit to the patient, and the patient will not be excluded from 
any other aspect of the main study. 
4.2 
Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
1. 
Known distant metastatic disease at study entry. Investigators are not required to 
specifically screen patients for distant metastasis beyond their normal Standard of 
Care practices and the protocol-specific post-operative imaging assessments, but 
any patient with known distant metastatic disease at screening must be excluded. 
2. 
Diagnosis of anaplastic thyroid cancer, medullary thyroid cancer, or Hürthle cell 
carcinoma (refer to inclusion criterion 4 for further details on Hürthle cell 
eligibility). 
3. 
Presence of anti-Tg antibodies at screening (as determined by standardised central 
methodology, refer to Section 6.4.3.4). 
4. 
Previous treatment with 131I (RAI) or external beam radiation therapy (EBRT) at 
any time in the past. 
5. 
Any unresolved toxicity  CTCAE Grade 2 from previous anti-cancer therapy 
including the patient’s recent thyroid cancer surgery. 
6. 
Having received an investigational drug during the last 4 weeks prior to first dose of 
study treatment. 
7. 
Recombinant human TSH (rhTSH, Thyrogen):  


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
50(118) 
(a) 
Patients with known hypersensitivity to rhTSH will be excluded. 
(b) 
Patients not willing to use rhTSH prior to their RAI treatment will also be 
excluded (ie, patients or clinicians choosing withdrawal of thyroid hormone 
treatment prior to their RAI treatment will be ineligible for this study). 
8. 
Patients requiring medication with high content in iodide (amiodarone), or patients 
receiving IV iodine containing contrast as part of radiographic procedure within the 
last 3 months prior to the planned RAI treatment (unless a urine measurement 
demonstrates that urinary iodide level has returned to normal range earlier than 3 
months following administration of a contrast agent). 
9. 
Patients with clinically significant cardiovascular disease as defined by the 
following:  
(a) 
Uncontrolled hypertension (BP 150/95 despite optimal therapy) 
(b) 
LVEF < 55% measured by echocardiography (or MUGA) 
(c) 
Symptomatic heart failure (NYHA grade II-IV), prior or current 
cardiomyopathy, or severe valvular heart disease 
(d) 
Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite 
medical therapy) 
(e) 
Atrial fibrillation with a ventricular rate >100 bpm on ECG at rest 
(f) 
Acute coronary syndrome within 6 months prior to starting treatment 
(g) 
Mean QTc interval >470 ms  
10. 
Patients with the following ophthalmological findings/conditions: 
(a) 
Intraocular pressure >21 mmHg, or uncontrolled glaucoma (irrespective of 
intraocular pressure) 
(b) 
Current or past history of central serous retinopathy or retinal vein occlusion 
11. 
Patients with a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to agents used in the study. 
12. 
Any evidence of severe or uncontrolled systemic disease, active infection, active 
bleeding diatheses or renal transplant, including any patient known to have hepatitis 
B, hepatitis C or human immunodeficiency virus (HIV). 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
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Date 3rd April 2013 
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13. 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection or psychiatric illness/social situations that would limit compliance with 
study requirements. 
14. 
Pregnant women will be ineligible (breast feeding should be discontinued if the 
mother is treated with study therapy). 
15. 
Male or female patients of reproductive potential who are not employing an 
effective method of contraception (refer to Section 5.1.2). 
16. 
Refractory nausea and vomiting, chronic gastrointestinal diseases, or significant 
bowel resection that in the Investigator’s opinion would preclude adequate 
absorption of study therapy. 
17. 
History of another primary malignancy within 5 years prior to starting study 
treatment, except for adequately treated basal or squamous cell carcinoma of the 
skin or cancer of the cervix in situ and the disease under study.  
18. 
Clinical judgement by the investigator that the patient should not participate in the 
study. 
19. 
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site). 
20. 
Previous treatment with any MEK or BRAF inhibitor. 
21. 
Previous enrolment or treatment in the present study. 
4.2.1 
Genetics research study (optional blood sample) 
1. 
Exclusion criteria for participation in the optional genetics research component of 
the study: 
(a) 
Previous allogeneic bone marrow transplant 
(b) 
Whole blood transfusion within 120 days of the date of genetic sample collection 
(except for leukocyte depleted blood transfusion, which is allowed) 
For procedures for withdrawal of incorrectly enrolled patients see Section 5.3. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
52(118) 
5. 
STUDY CONDUCT 
5.1 
Restrictions during the study 
5.1.1 
Low-iodine diet 
Published data and opinion regarding the necessity for a low iodine diet prior to RAI therapy 
or a diagnostic whole body scan is variable.  For the purpose of this study a low iodine diet 
will be mandated in order to standardise patient care and study data as best as possible. 
Compliance to the low iodine diet will not be recorded or assessed, and all randomised 
patients will receive RAI treatment as planned. Refer to Table 2 and the Study Plan (Table 3) 
for further details. An example low iodine diet is provided as Appendix F to this protocol. 
A low iodine diet is necessary at two occasions in the study: 
Prior to RAI adjuvant treatment 
All patients must be willing to adhere to the low iodine diet for a period of 1 week before their 
planned RAI adjuvant treatment, until the day after their RAI therapy. 
Prior to the primary endpoint Stage 2 assessments 
All patients must be willing to adhere to the low iodine diet for a period of 1 week before the 
diagnostic 131I dose used prior to the primary endpoint WBS assessment (131I nuclear medicine 
scan), until the diagnostic WBS assessment is completed. This is only relevant for patients 
who pass Stage 1 primary endpoint assessments (refer to Section 6.4.2). 
5.1.2 
Other study restrictions 
The following restrictions also apply while the patient is receiving selumetinib or placebo:  
1. 
Female patients of child-bearing potential will be required to use reliable methods 
of contraception until 4 weeks after the last dose of selumetinib/placebo or longer if 
required for standard RAI administration restrictions and in accordance with local 
labels.  Male patients will be required to use reliable methods of contraception until 
12 weeks after the last dose of the last study treatment, or longer if required for 
standard RAI administration restrictions and in accordance with local labels.  
Reliable methods of contraception should be used consistently and correctly.  
Acceptable methods include implants, injectables, combined oral contraceptives 
(which must all be combined with barrier methods of contraception), some IUDs 
and vasectomised partner.  Sexual abstinence is also an acceptable method of 
contraception according to ICHM3. 
2. 
Fasting restrictions for the study are described in Section 5.5.2.   
3. 
Patients should avoid excessive sun exposure and use adequate sunscreen protection 
if sun exposure is anticipated. 


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4. 
Patients should avoid large amounts of grapefruit and Seville oranges (and other 
products containing these fruits eg, grapefruit juice or marmalade) during the study 
treatment period. 
5. 
Selumetinib capsules contain D-Į- Tocopheryl polyethylene glycol 1000 succinate 
(TPGS, a water-soluble form of vitamin E) as an excipient.  Patients should not 
therefore 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.  The maximum dose of vitamin E patients may receive from selumetinib 
is approximately 210 mg/day. The concomitant intake of excessive 
(supratherapeutic) doses of vitamin E should be avoided. High doses of vitamin E 
have been reported to potentiate the anticoagulant activity of coumadins such as 
warfarin. Patients who are taking coumadin anticoagulants should increase the 
frequency of assessment of anticoagulation, such as INR measurements, upon 
initiation of dosing with study treatment. 
6. 
Permitted and excluded antiemetic medications in this study are described in 
Section 5.6.   
7. 
Permitted and excluded medications for management of skin toxicities (eg, rash) are 
described in Appendix G: “Guidance for Management of Adverse Events in Studies 
of Selumetinib.” All patients will be given prophylactic provision of emollient 
cream to take home and to start using when starting study treatment. 
8. 
Unless patients require re-treatment, they should not be enrolled in other studies 
evaluating novel therapies for thyroid cancer for the entire study duration. 
5.2 
Patient enrolment, randomisation and initiation of investigational 
product 
The Principal Investigator or delegate will: 
1. 
Obtain signed informed consent from the potential patient before any study specific 
procedures are performed. 
2. 
Determine patient eligibility. See Sections 4.1 and 4.2 
3. 
Call IVRS/IWRS to assign the eligible patient a unique enrolment number 
(beginning with ‘E#’), and randomisation code (subject number).  Randomisation 
codes will start at 001 and go up. 
Randomisation codes will be assigned strictly sequentially by IVRS/IWRS as patients are 
eligible for randomisation.  
If a patient withdraws from the study, then his/her enrolment/randomisation code cannot be 
reused. 


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If a patient withdraws from the study after they have been enrolled or have received study 
treatment then they cannot re-enter the study. 
5.2.1 
Procedures for randomisation 
Patients who satisfy all the entry criteria will be centrally assigned by the IVRS/IWRS, 
according to the randomisation scheme generated by the Biostatistics Group, AstraZeneca, to 
selumetinib or placebo in a ratio of 2:1.  
Every effort should be made to minimise the time between randomisation and starting 
treatment.  Patients must not be randomised unless all eligibility criteria have been met. 
IVRS/IWRS will be used for allocation of enrolment number, allocation of randomisation 
number, study medication assignment, discontinuation from study treatment, emergency code 
breaks and study drug shipment confirmation.   
5.3 
Procedures for handling patients incorrectly enrolled, randomised 
or initiated on investigational product 
Patients who fail to meet the inclusion/exclusion criteria should not, under any 
circumstances, be enrolled or receive study medication.  There can be no exceptions to this 
rule. Patients who are incorrectly enrolled but are not yet randomised or initiated on treatment 
should be withdrawn from the study. 
Where patients that do not meet the inclusion and/or exclusion criteria, are enrolled in error, or 
incorrectly started on treatment, or where patients subsequently fail to meet the study criteria 
post initiation, the investigator should inform the AstraZeneca Physician immediately.  
The AstraZeneca Physician must ensure all such contacts are appropriately documented. 
5.4 
Blinding and procedures for unblinding the study  
5.4.1 
Methods for ensuring blinding 
The active and placebo capsules will appear identical and presented in the same packaging to 
ensure blinding of the medication.  Medication will be labelled using a unique material pack 
code which is linked to the randomisation scheme.  IVRS/IWRS will allocate randomisation 
numbers sequentially when sites call IVRS/IWRS to randomise an eligible patient.  
IVRS/IWRS will allocate the medication pack code to be dispensed to the patient. 
All patients must remain blinded until after the 18 month primary endpoint data analysis has 
been conducted for the study; most patients will thus remain blinded for longer periods of time 
than their initial 18 month follow up period.  Any patient that is re-treated prior to the 18 
month primary endpoint time-point (refer to guidelines in Section 5.9), must not be unblinded 
until after the primary analysis of 18 month primary endpoint data from all patients in the 
study. 


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The personnel analyzing the PK samples will be unblinded to treatment allocation in order to 
organise the appropriate sample analysis. The treatment allocation information will be kept in 
a secure location until the end of the study. 
Once the 18 month primary endpoint data analysis has been conducted for the study, patients 
may be unblinded for the remaining study follow up. 
5.4.2 
Methods for unblinding the study 
Individual treatment codes, indicating the treatment randomisation for each randomised 
patient, will be available to the investigator(s) or pharmacists from the IVRS/IWRS.  
Procedures for emergency unblinding will be described in the IVRS/IWRS user manual that 
will be provided to each centre. 
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomisation. The 
investigator documents and reports the action to AstraZeneca, without revealing the treatment 
given to patient to the AstraZeneca staff. 
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational product and that potentially require 
expedited reporting to regulatory authorities.  Treatment codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each individual 
patient have been made and documented. 
5.5 
Treatments 
5.5.1 
Identity of investigational product(s) 
Investigational product 
Dosage form and strength 
Manufacturer 
Selumetinib 
 
25 mg Hyd-Sulfate capsule 
AstraZeneca 
Placebo to match selumetinib 
Capsule  
AstraZeneca 
 
5.5.2 
Doses and treatment regimens 
Patients will be randomised on a 2:1 basis, via IVRS/IWRS, to receive either selumetinib 
75 mg twice daily, or matching placebo. 
Patients will be instructed to take 3 capsules orally on an empty stomach (no food or drink 
other than water for 2 hours prior to dosing and 1 hour after dosing), twice a day 
approximately 12 hours apart according to the Study Plan.  Capsules should be taken with 
water only.  On clinic days when PK samples are scheduled to be taken, dosing should be 
delayed until arrival at the clinic and until the pre-dose PK sample has been taken.  
Selumetinib/placebo will be supplied in bottles of 60 capsules of 25 mg strength. At 
Randomization visit, selumetinib/placebo for the entire treatment period will be dispensed (5 


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bottles). Individual bottles will be dispensed in accordance with the medication identification 
numbers provided by the IVRS/IWRS. 
Day 1 of study treatment must occur within 16 weeks of the patient’s thyroid cancer surgery 
(their last surgery if it was a 2-stage thyroidectomy).   
5.5.3 
Management of study treatment related toxicity 
The immediate management of any adverse event should be according to standard clinical 
practice for that event. Subsequent management of treatment related adverse events should be 
guided by the Investigators’ assessment of causality. 
5.5.3.1 
Selumetinib dose interruption or reduction 
It is essential that patients remain on study treatment continuously for a minimum of 7 
consecutive days prior to their planned RAI therapy, on the day of RAI therapy, and for 5 
consecutive days afterwards.  If necessary, RAI therapy may be rescheduled at the discretion 
of the Investigator until the patient has been on study treatment for a minimum of 7 
consecutive days (as long as the total duration of study treatment does not exceed 43 days, this 
allows the planned RAI to be postponed by up to 1 week if absolutely necessary). 
For all adverse events reported in this study that are considered at least partly causal to 
administration of selumetinib, the following dose modification guidance should be applied.   
Study treatment with selumetinib/placebo should be temporarily interrupted if one of the 
following AEs are observed (and considered causal to study treatment), despite optimal 
supportive care (ie, supportive treatment may be given prior to withholding study treatment): 
x
Any intolerable adverse event regardless of Grade 
x
Any adverse events  CTCAE Grade 3 
On improvement of the adverse event to Grade 1 (Grade 2 for rash) or baseline, study 
treatment may be restarted at the original dose or may be reduced at the discretion of the 
investigator. One dose reduction of study treatment to 50 mg twice daily is permitted before 
permanent discontinuation.   
x
If a further episode of the same AE subsequently requires dose interruption, 
selumetinib may be restarted at the next dose level down on improvement of the 
AE. 
x
If a different AE subsequently requires dose interruption, selumetinib may be 
restarted at the same dose or at the next dose level down on improvement of the AE.   
x
Selumetinib should not be re-escalated to an earlier dose level on improvement of 
an AE.  


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x
The schedule of assessments described in Table 3 should continue relative to Day 1 
in the event of selumetinib dose interruption or reduction. 
Therefore, the dose reduction/adjustment algorithm in the study allows for 2 steps only:  
75 mg twice daily (initial dose) 
Ļ 
50 mg twice daily 
Ļ 
permanent discontinuation 
All dose delays, reductions and adjustments will be recorded in the appropriate electronic 
Case Report Form (eCRF). 
The guidance above should also be followed for dose interruptions or reductions for adverse 
events of rashes or diarrhoea. Guidance for interruption or reduction of treatment with 
selumetinib may be considered for particular events, as indicated in the algorithms provided as 
a separate study aid in the “Guidance for Management of Specific Adverse Events in Studies 
of Selumetinib” (refer to Section 5.5.3.2).   
5.5.3.2 
Management and investigation of specific selumetinib related AEs 
Recommendations for the management or investigation of the following specific AEs is 
provided in Appendix G: Guidance for Management of Adverse Events in Studies of 
Selumetinib. 
x
Rash: early initiation of treatment for rash is strongly recommended to minimise the 
duration and severity of the adverse event. All patients should be given prophylactic 
provision of emollient cream to take home and to start using when starting study 
treatment as indicated in the algorithm for management and investigation of rash 
included in Appendix G. 
x
Visual disturbances: symptoms, including blurred vision, have been reported during 
treatment with selumetinib. Events consistent with central serous retinopathy have 
been reported in a small number of patients receiving treatment with selumetinib, 
generally in combination with other novel targeted anti-cancer agents. AEs of 
central serous retinopathy and retinal vein occlusion have been reported in studies 
of other MEK inhibitors (Lemech & Arkenau 2012). Investigation to determine the 
underlying cause of visual disturbance is recommended. 
x
Diarrhoea: early initiation of treatment for diarrhoea is strongly recommended to 
minimise the duration and severity of the adverse event. Treatment provision will 
be according to Investigator discretion according to local practice and regulations.  
x
Dyspnoea: new or worsening dyspnoea has been reported during treatment with 
selumetinib; investigation to determine the underlying cause is recommended. 


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5.5.4 
Additional study drugs 
5.5.4.1 
Thyrogen (rhTSH, thyrotropin alfa for injection) 
Thyrogen use prior to the RAI ablative dose 
Effective use of RAI therapy requires stimulation by TSH in order to maximise RAI uptake by 
thyroid cells. Recombinant human TSH (rhTSH or Thyrogen) will be used to stimulate iodide 
uptake according to the manufacturer’s recommendation (0.9 mg intra-muscular injection for 
2 days immediately prior to the RAI treatment according to the Study Plan Table 3). rhTSH is 
approved for use in routine clinical care as a diagnostic tool to stimulated serum thyroglobulin 
and RAI uptake for diagnostic scanning and as an adjunct to RAI ablation in many countries. 
This allows patients to avoid the hypothyroidism state, since they can maintain their routine 
thyroid hormone supplementation. Patients or clinicians choosing withdrawal of thyroid 
hormone treatment for this purpose will be ineligible for this study. All randomised study 
patients will receive Thyrogen twice prior to their RAI treatment dose. 
Thyrogen use for the primary endpoint assessments (18 months post-RAI) 
For those patients that progress to Stage 2 of the primary endpoint assessments (refer to 
Section 6.4.2),  Thyrogen will be used to stimulate iodide uptake immediately prior to 
administering the diagnostic 131I dose for the primary endpoint WBS assessment.  Patients will 
receive a 0.9 mg intra-muscular Thyrogen injection for two consecutive days.  Refer to 
Section 6.4.2.2 for further details. 
5.5.4.2 
Radioactive iodine (RAI) 
All RAI for the study will be locally provided at each site. 
Therapeutic RAI dose (131I) 
A single oral RAI dose of 100 mCi (3.7 GBq) 131I (+/- 10% at the time of administration) will 
be administered to all patients according to the Study Plan Table 3, according to standard 
practice at each site. 
Diagnostic WBS dose (131I) 
For those patients that progress to Stage 2 of the primary endpoint assessments (refer to 
Section 6.4.2),  a single oral RAI dose of 5 mCi (185 MBq) 131I (+/- 10% at the time of 
administration) will be administered for the primary endpoint WBS (nuclear medicine scan) 
18 months following the ablative treatment dose of RAI. Refer to the Study Plan Table 3, and 
Section 6.4.4.2 for further details. 
5.5.4.3 
Thyroid hormone supplementation (TSH suppression) 
Routine thyroid hormone supplementation (levothyroxine, LT4) is required during the study 
as per standard clinical practice. The purpose of this is both to correct resulting 
hypothyroidism using a dosage appropriate to achieve normal blood levels of thyroid 
hormone, and to inhibit TSH-dependant growth of residual thyroid cancer cells. Thyroid 


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hormone supplementation will be adjusted in individual patients with the aim of achieving 
suppressed TSH levels of <0.5 mIU/L for the duration of the study. 
5.5.5 
Study drug labelling 
Each bottle of selumetinib and matching placebo capsules will be labelled by Pharmaceutical 
Development Supply Chain, AstraZeneca or its designee. 
All labels will comply with good manufacturing practice (GMP) regulations, and will state 
that the drug is for clinical use only or that it is the investigational drug and is to be used by 
qualified investigators only and should be kept out of reach of children. The labels will have 
blank spaces for the site personnel to complete the following at the time of drug dispensing: 
enrolment code, visit number and dispensing date.  
Label text will be translated into local language. 
Each bottle of selumetinib/placebo capsules will have a tear-off portion that will be removed 
at the time of dispensing and attached to the Drug Label Accountability Log.  
5.5.6 
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions.  The 
investigational product label on the bottle specifies the appropriate storage. 
5.6 
Concomitant medications 
The use of antiemetic medication for the prevention of nausea caused by administration of 
radioactive iodine is permitted in this study according to local clinical practice (with the 
exception of aprepitant which is an excluded medication in this study, due to the potential for 
modification of selumetinib exposure via CYP3A4). The administration of any antiemetic 
medication must be recorded in the appropriate sections of the Case Report Form. 
All patients will be given prophylactic provision of emollient cream to take home and to start 
using when starting study treatment as indicated in the algorithm for management and 
investigation of rash included in Appendix G: “Guidance for Management of Adverse Events 
in Studies of Selumetinib.” 
The following treatments/drugs are restricted in this study: 
x
No other anti-cancer agents, or investigational drugs should be administered whilst 
patients are receiving study medication or are in follow-up in this study (unless the 
patient withdraws from the study, or meets the re-treatment criteria in Section 5.9).   
x
Patients who are taking coumarin anticoagulants should increase the frequency of 
assessment of anticoagulation, such as INR measurements, during the study 
treatment period with selumetinib/placebo.   


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x
The maximum dose of vitamin E patients may receive from selumetinib is 
approximately 210 mg/day. The concomitant intake of excessive (supratherapeutic) 
doses of vitamin E should be avoided in patients receiving the capsule formulation. 
x
Throughout the study, patients should avoid changes to, or the addition of all other 
concomitant medications, in particular any that may affect the metabolism of 
selumetinib (eg, CYP1A2 or 3A4 inhibitors/inducers), unless considered clinically 
indicated. 
Other medication, which is considered necessary for the patient’s safety and well being, may 
be given at the discretion of the investigator and recorded in the appropriate sections of the 
Case Report Form.  
All concomitant medications will be recorded on the CRF until 30 days after the last dose of 
study treatment, and after this time a study-specific record must be kept of any further 
treatment for thyroid cancer (including surgery), or treatment for RAI-related AEs/SAEs until 
the last study visit for all patients (refer to Section 5.9). 
5.7 
Treatment compliance 
The administration of all study drugs (including investigational products) should be recorded 
in the appropriate sections of the Case Report Form. 
5.7.1 
Accountability 
The study drug provided for this study will be used only as directed in the study protocol. 
The study personnel will account for all study drugs dispensed to and returned from the 
patient. 
Where appropriate facilities and procedures for drug destruction exist, and prior approval from 
the site monitor has been received, site personnel will account for all unused drugs and for 
appropriate destruction. 
Where such facilities do not exist study site personnel/study monitor will return all unused 
drugs to AstraZeneca or its designee according to country rules. 
The AstraZeneca monitors will ensure that all drug-handling procedures at sites are 
appropriate, and that all certificates of delivery and return are completed and signed by the 
site, AstraZeneca, or its delegate, as appropriate.  In addition, the monitor will check that the 
certificate of destruction has been signed by the site, if study drug destruction is performed at 
the site. 
5.8 
Discontinuation of investigational product 
Patients may be discontinued from investigational product (IP) in the following situations: 


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x
Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment 
x
Adverse Event 
x
Risk to patients as judged by the investigator and/or AstraZeneca 
x
Severe non-compliance to protocol as judged by the investigator and/or 
AstraZeneca 
x
A female patient becoming pregnant 
5.8.1 
Procedures for premature discontinuation of a patient from investigational 
product  
A patient that decides to prematurely discontinue investigational product will always be asked 
about the reason(s) and the presence of any adverse events.  If possible, they will be seen and 
assessed by an investigator(s).  Adverse events will be followed up (See Sections 6.5.3 and 
6.5.4), and all study drugs should be returned by the patient.  In this situation, a treatment 
discontinuation visit will be conducted as soon as possible after the patient received the last 
dose of study drug (selumetinb/placebo). A single 12-lead ECG is also required at premature 
discontinuation of treatment. 
If a patient is withdrawn from the study (ie, withdraws consent for follow-up procedures), see 
Section 5.10. 
Collection of all AEs/SAEs will continue until 30 days after the last dose of study drug 
(selumetinib/placebo) for prematurely withdrawn patients. As long as the patient does not 
withdraw consent, follow up in this study will continue as planned. 
Any patient with an AST, ALT or bilirubin value above ULN at time of the last dose of 
selumetinib/placebo should have a further liver chemistry profile (AST, ALT, bilirubin and 
ALP) performed 30 days (±7days) after discontinuation. 
5.9 
Criteria for further thyroid cancer therapy during the study 
5.9.1 
Re-treatment prior to the 18 month primary endpoint assessments 
It is acknowledged that there is variability in thyroid cancer re-treatment clinical practice.  The 
study-specific criteria below are designed to standardise re-treatment prior to the primary 
endpoint assessments for the purpose of this study as best as possible. Thus, further thyroid 
cancer therapy (eg, additional surgery or RAI treatment) prior to the primary analysis of 
complete remission at 18 months post-RAI, must not be administered unless any of the 
following criteria are met.  
Patients meeting the following re-treatment criteria do not have to be re-treated, they can 
instead be followed expectantly without re-treatment at the discretion of the treating 
Investigator. 


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5.9.1.1 
Biochemical disease re-treatment criteria 
The first scheduled post-RAI follow up for serum Tg will be assessed 9 months after the RAI 
dose (± 3 months). Tg assessment for this purpose may take place at any time from 6 months 
after the patient’s RAI treatment (but not before 6 months).   
All biochemical sample analysis for study re-treatment criteria must be performed by 
standardised central laboratory methodology (for further details refer to the Laboratory 
Manual). 
Patients must not be re-treated for thyroid cancer unless any of the following biochemical 
criteria are met: 
1. 
If a serum Tg level  5 ng/mL on central analysis is measured during TSH 
suppression, then a repeat Tg sample must be assessed by central analysis 2-4 
weeks later. The patient must not be re-treated unless both centrally analysed 
samples demonstrate the suppressed Tg level to be 5 ng/mL or higher.   
2. 
If a serum Tg level  10 ng/mL is measured following TSH stimulation, the 
patient may be re-treated (a repeat sample for confirmation is not necessary). Note, 
a stimulated Tg assessment is not part of the study-specific follow up plan for 
patients prior to the 18 month primary endpoint assessments (thus it is not 
recommended or required, and is not included in the Study Plan). However, if a 
stimulated Tg assessment is performed due to local practice, this re-treatment 
criterion applies.  
3. 
If an increase (delta change) in serum Tg level of 3 ng/mL or more is determined 
between two Tg assessments taken 2-4 weeks apart (due to a repeat sample), the 
patient may be re-treated.  
Thus, in the absence of structurally identifiable disease, patients in this study should have 
continued observation without additional thyroid cancer treatment (eg, additional RAI, 
surgery) until the study primary endpoint (18 months after RAI treatment), if the serum Tg 
level remains below 5 ng/mL during TSH suppression, below 10 ng/mL following TSH 
stimulation (if assessed), and is either stable/declining, or rising less than 3 ng/mL between 
samples 2-4 weeks apart.   
Note: If a patient has Tg levels below the above re-treatment criteria, but TgAb are detected 
(ie, the patient is TgAb positive; refer to Section 6.4.3.4), the patient should not be re-treated 
unless new structural disease is detected according to Section 5.9.1.2 (ie, it is recommended 
that patients are not re-treated on the basis of new antibodies alone, in the absence of 
structural disease).  
Unscheduled samples and local analysis 
It is acknowledged that Investigators may wish to also perform their own local biochemical 
analysis according to local standard of care. In general, unscheduled samples that are taken 


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either outside of the visit window specified, or in addition to the scheduled study samples, 
should not be sent for standardised central analysis. Only if such unscheduled local analysis 
leads the Investigator to wish to administer further therapy for thyroid cancer, should a sample 
ideally be sent for central analysis and the above criteria applied before the patient is re-
treated.   
5.9.1.2 
Structural disease re-treatment criteria 
The first post-RAI ultrasound follow up will be assessed 9 months after the RAI dose (± 3 
months). Ultrasound assessment for this purpose may take place at any time from 6 months 
after the patient’s RAI treatment (but not before 6 months).  
Patients must not be re-treated for thyroid cancer unless any of the following structural criteria 
are met: 
1. 
In the absence of any biochemical evidence of thyroid cancer, structural DTC 
should be confirmed prior to re-treatment, by positive histology/cytology from a 
biopsy/FNA of ultrasonographically suspicious lesions or lymph nodes  5 mm in 
the smallest diameter (refer to Section 6.4.4.5).  
2. 
Identification of new distant metastases (these do not need to be confirmed by 
biopsy). Assessment of potential distant metastases is not required, but may be 
performed if clinically indicated at the discretion of the treating Investigator. 
5.9.1.3 
Patient management on study (up to the primary analysis at 18 months post-
RAI) 
At the required follow up visits, the following questions should be answered for each subject: 
1. 
Does the patient have a suppressed Tg  5 ng/mL, a TSH stimulated Tg  10 ng/mL 
or a rising Tg level (increase of 3 ng/mL or more) according to the guidelines in 
Section 5.9.1.1? 
2. 
Does the patient have new loco-regional structural thyroid cancer according to the 
guidelines in Section 5.9.1.2? 
3. 
Does the patient have new distant metastatic lesions according to the guidelines in 
Section 5.9.1.2? 
If the answer is yes to any of the questions, the patient is unlikely to enter remission and may 
be re-treated for thyroid cancer (but does not have to be).  
Full details of any thyroid cancer re-treatment must be recorded on the appropriate eCRF. 
Any re-treated patients will remain in the study and should enter standard of care follow up 
according to local practice until 3 years after their initial RAI therapy (refer to Section 6.4.8).  
Patients who are re-treated prior to the primary endpoint at 18 months post-RAI do not require 
primary endpoint disease assessments performing, however these patients should continue to 


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follow all protocol-scheduled visits for safety (AE/SAE follow-up) as described in the Study 
Plan Table 3 and in Section 6.5.  Patients do not need to attend these follow up visits in person 
(telephone contact is permitted), however when local follow-up visits coincide with protocol-
specified visits, these should ideally be in person where possible. 
If the answer is no to all questions, the patient should continue the study follow-up as per 
protocol without additional thyroid cancer re-treatment. 
5.9.2 
Re-treatment after the 18 month primary endpoint assessments 
Following completion of all assessments for complete remission at the primary endpoint 
18 months post-RAI, patients may receive re-treatment for thyroid cancer as per clinically 
indicated according to local standard of care.  Any re-treated patients will remain in the study 
and should enter standard of care follow up according to local practice until 3 years after their 
initial RAI therapy (refer to Section 6.4.8). 
Full details of any thyroid cancer re-treatment must be recorded on the appropriate eCRF. 
5.10 
Withdrawal from study 
Patients are at any time free to withdraw from study (investigational product and follow-up 
assessments), without prejudice to further treatment (withdrawal of consent).  Such patients 
will always be asked about the reason(s) and the presence of any adverse events.  If possible, 
they will be seen and assessed by an investigator.  Adverse events will be followed up (see 
Sections 6.5.3 and 6.5.4); any remaining study drug should be returned by the patient. 
5.11 
Replacement of patients 
There will be no replacement of randomised patients in this study for any reason. 
6. 
COLLECTION OF STUDY VARIABLES 
6.1 
Recording of data 
A Web Based Data Capture (WBDC) system will be used for data collection and query 
handling.  The investigator will ensure that data are recorded on the electronic Case Report 
Forms as specified in the study protocol and in accordance with the instructions provided. 
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed electronic Case Report Forms.  A copy of the completed 
electronic Case Report Forms will be archived at the study site. 
6.2 
Data collection at enrolment 
The following data will be collected & procedures performed for each patient: 
1. 
Informed consent (to include consent for archival tumour sample provision) 


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2. 
Demography (date of birth, sex, race) 
3. 
Histological/cytological confirmation of thyroid cancer, including post-operative 
disease staging 
4. 
Medical and surgical history  
5. 
Concomitant medications and previous anti-cancer therapy 
6. 
Assessment of WHO or ECOG performance status (refer to Section 6.2.1) 
7. 
Collection of AEs will start after signing the consent form 
8. 
Physical examination  
9. 
Vital signs (resting blood pressure (BP), pulse rate), weight and height 
10. 
Single ECG 
11. 
Blood samples for clinical chemistry and haematology 
12. 
Blood sample for determination of interfering Tg antibodies (central standardised 
analysis) 
13. 
Urinalysis (at sites where the local laboratory is able to determine the required 
parameters, see Section 6.5.5) 
14. 
Pregnancy test for female pre-menopausal patients  
15. 
Full ophthalmologic examination, including slit-lamp fundoscopy and intraocular 
pressure examination  
16. 
ECHO or MUGA  
17. 
The following imaging assessments must be performed within the 28 day screening 
period but only after all other screening procedures have confirmed eligibility status 
(refer to Section 6.3): 
(a) 
Neck ultrasound (US) 
(b) 
Neck MRI with contrast 
(c) 
Chest CT scan without contrast 
18. 
Overall assessment of patient eligibility for the study 


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19. 
Upon confirmation of patients’ eligibility, patients will be invited to attend the 
randomisation visit.  Patients must not be randomised unless all eligibility criteria 
have been met. 
20. 
Call interactive voice response system (IVRS)/interactive web response system 
(IWRS) to randomise the patient 
6.2.1 
Performance status definitions 
Performance status will be assessed at screening according to either the WHO or ECOG 
criteria as follows: 
0 = Fully active, able to carry out all pre-disease performance/activities without restrictions 
1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature e.g., light housework, office work 
2 = Ambulatory and capable of self-care, but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 = Completely disabled, cannot carry on self-care, totally confined to bed or chair. 
6.3 
Post-operative imaging assessments for eligibility 
The post-operative imaging assessments of US, neck MRI and chest CT are performed during 
screening to determine study eligibility. These assessments must determine the absence of 
macroscopic persistent disease post-surgery for a patient to be eligible prior to randomisation. 
The post-operative imaging assessments must be scheduled once all other screening 
assessments and eligibility criteria have been verified. 
The screening chest CT procedure must be performed without iodine containing contrast 
agent.  
Eligibility will be determined by the local investigational site. 
Acquisition guidelines for the post-operative imaging assessments will be provided separately 
to this protocol. 
In addition to information recorded on the eCRF for US, the post-operative images for chest 
CT and neck MRI must be collected and sent to the central imaging CRO. 
6.4 
Efficacy  
6.4.1 
Complete remission  
The primary endpoint for this study is complete remission rate at 18 months (following RAI 
treatment). 


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Definition of complete remission: 
Patients will be defined to be in complete remission if all of the following criteria can be 
demonstrated: 
1. 
Serum Tg levels < 1ng/mL during rhTSH stimulation, in the absence of interfering 
Tg antibodies, as assessed by standardised central laboratory analysis. 
2. 
No confirmed evidence of thyroid cancera on neck US, as assessed by investigator 
site review. 
3. 
No confirmed radiological evidence of thyroid cancera, as assessed by blinded 
independent central review.  
4. 
No histopathological evidence of thyroid cancer on FNA/biopsy when performed, 
as assessed by investigator site review. 
5. 
No further thyroid cancer therapy was administered in the first 18 months following 
the initial RAI treatment. 
There are two main components to complete remission: biochemical remission and structural 
remission. Biochemical remission is measured by Tg and structural remission is assessed by 
the imaging assessments US, MRI, CT and WBS in conjunction with biopsy/FNA.  
A staged approach will be taken for performing assessments contributing to the primary 
endpoint, to avoid unnecessary assessments for individual patients who received further 
therapy prior to the primary assessment, and for those patients not in biochemical remission 
(as determined by serum Tg levels in the absence of interfering Tg antibodies). 
aConfirmation of evidence of structural DTC will be either histopathological (from a 
biopsy/FNA; as criterion 4 above), or RAI-avid disease (refer to Section 6.4.4.2). In this 
disease setting, structural abnormalities that are not RAI-avid and do not have confirmed 
histopathology consistent with DTC (ie are not biopsy proven) are considered benign in the 
absence of biochemical DTC. 
6.4.2 
Staged approach to primary endpoint assessments 
Full details of the staged approach to the primary endpoint assessments are outlined below.  
There will be 3 stages of assessments. Patients that have been re-treated for thyroid cancer 
will not have any primary endpoint assessments performed. All patients who have not been re-
treated for thyroid cancer will have stage 1 assessments performed. The decision on whether 
to proceed to stage 2 and 3 assessments for patients that have not been re-treated will be based 
on centrally analysed biochemical data (Tg and TgAb data).  
Sites will receive results from standardised central laboratory analysis of the biochemical data 
and make a decision to proceed based on these results. Patients identified as not in 


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biochemical remission will not be required to have all imaging assessments described in 
Section 6.4.1 performed. 
For patients that have imaging assessments performed, the appropriate data will be sent to the 
imaging CRO for blinded independent central review to identify presence or absence of 
structural disease. Note: results from the central imaging review will not be reported to 
clinical sites. 
Briefly: 
In stage 1, suppressed Tg will be determined together with neck US assessment for all patients 
who did not require re-treatment for thyroid cancer during the first 18 months of follow up 
(refer to Section 6.4.2.1).  
In stage 2, rhTSH stimulated Tg and diagnostic WBS will be performed (refer to 
Section6.4.2.2). 
In stage 3, additional radiological imaging (chest CT and neck MRI) will be performed (refer 
to Section 6.4.2.3).   
Stage 1 assessments must be started 18 months ± 2 weeks following the patient’s RAI dose, 
and all necessary primary endpoint assessments (all 3 stages if required) must be completed 
within an 8 week period (refer also to Table 4). 
Refer to the flowchart Figure 3 for a visual representation of the staged approach for primary 
endpoint assessments. 
Refer to Section 6.4.5 for the process of determining complete remission from the primary 
endpoint assessment data. 


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Figure 3 
Flow chart for staged primary endpoint assessments 
 


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6.4.2.1 
Primary endpoint assessments Stage 1 
Patients that have been re-treated for thyroid cancer between their initial RAI dose and the 
primary endpoint assessments 18 months later (refer to Section 5.9 for re-treatment criteria), 
will not have any primary endpoint assessments performed. For the purpose of the primary 
endpoint, such re-treated patients will be determined not to be in complete remission. 
In stage 1, all patients that have not previously been re-treated for thyroid cancer will have: 
x
Suppressed Tg level determined by standardised central laboratory analysis.  
x
TSH and TgAb (using the same blood draw for suppressed Tg) determined by 
standardised central laboratory analysis. Refer to Section 6.4.3. 
x
Neck US assessment for structural disease to be assessed by investigator site 
review. Refer to Section 6.4.4.1. 
Suspicious lesions identified by US  5 mm in the shortest diameter should be biopsied or 
aspirated by fine needle. All biopsy/FNA samples will be assessed locally at each site. Lesions 
identified by US < 5 mm in the shortest diameter do not require a biopsy. 
All neck US and biopsy/FNA samples will be assessed locally at each site. The relevant US 
information with any biopsy findings will be provided to the imaging CRO as part of the 
blinded independent central review. 
When to proceed to stage 2 assessments 
All patients in the following situations should proceed to stage 2 assessments: 
1. 
Patients with suppressed Tg < 1 ng/mL. These patients should proceed to stage 2 
regardless of the TgAb or US results. 
2. 
Patients who are TgAb positive in stage 1 (regardless of the suppressed Tg level, 
and US results). 
3. 
Patients who fulfil either of the 2 above criteria, and have a biopsy/FNA result 
pending (ie, Investigators should not wait for the biopsy/FNA result before 
performing stage 2 assessments). 
When not to proceed to stage 2 assessments 
All patients in the following situations will be classified not in complete remission and should 
not proceed to stage 2 assessments: 
1. 
Patients who have suppressed Tg level  1 ng/mL in the absence of TgAb 
(unequivocal biochemical disease). 


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2. 
Patients with a positive biopsy/FNA that confirms the presence of structural DTC. 
Note that if the biopsy/FNA results are not yet available, the patient should not 
delay proceeding to stage 2 assessments. 
Patients who demonstrate presence of disease and do not proceed to stage 2 assessments will 
enter standard of care treatment/follow up at each centre as determined by the treating 
Investigator, and will continue to be followed in this study until 3 years following their 
initial RAI dose (refer to Section 6.4.6). 
6.4.2.2 
Primary endpoint assessments Stage 2 
In stage 2, patients will have: 
x
rhTSH stimulated Tg level determined by standardised central laboratory analysis.  
x
TgAb (from the same blood draw for rhTSH stimulated Tg) determined by 
standardised central laboratory analysis. TSH will not be analysed from this sample. 
A repeat (third) sample for TgAb analysis may be required 10 days ± 3 days later if 
the stage 1 and 2 TgAb status is discordant (refer to Table 5). 
x
Diagnostic nuclear medicine 131I scan (WBS) to be evaluated by blinded 
independent central review. 
These assessments will require the patient to follow a low iodine diet for a period of 1 week 
before the diagnostic 131I dose, until the diagnostic WBS assessment is completed (refer to 
Section 5.1.1 and Appendix F). Patients will also receive two Thyrogen injections (refer to 
Section 5.5.4.1) on consecutive days (day 1 and 2), followed by a diagnostic dose (5 mCi) of 
131I on either day 2 or day 3, and a blood draw for stimulated Tg central assessment and WBS 
both on day 5. 
When to proceed to stage 3 assessments 
Patients should proceed to stage 3 assessments in the absence of biochemical disease. Patients 
with stimulated Tg < 1 ng/mL and TgAb negative (for the definition of TgAb negativity refer 
to Section 6.4.3.4) should proceed to stage 3 regardless of the WBS results. 
x
Note that if the stage 1 and 2 blood samples are discordant for TgAb, a repeat 
(third) blood sample for central analysis is required 10 days (±3 days) later. Only if 
the third sample is negative for TgAb will the stimulated Tg level from stage 2 be 
considered to be interpretable and valid for decision making. Refer also to Table 5. 
x
Note also that for study purposes the WBS will evaluated by blinded independent 
central review, and even if local interpretation of WBS scan data indicates uptake 
suspicious for DTC, any biochemically negative patients must still be sent for stage 
3 assessments (in case the local and central WBS results are discordant). 


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When not to proceed to stage 3 assessments 
All patients in the following situations will be classified not in complete remission and should 
not proceed to stage 3 assessments: 
1. 
Patients who have stimulated Tg level  1 ng/mL in the absence of TgAb 
(unequivocal biochemical disease by standardised central laboratory analysis). 
2. 
Patients confirmed to be TgAb positive (regardless of all other data): 
(a) 
When both the stage 1 and 2 blood samples are TgAb positive (refer to 
Section 6.4.3.4). 
(b) 
When the repeat (third) blood sample confirms positive TgAb following a 
discordant TgAb status from stage 1 and 2.  
In these situations the stimulated Tg value will be deemed to be uninterpretable, and the 
patient will be deemed not to be in complete remission because absence of biochemical 
disease cannot be proven.  
These patients will enter standard of care treatment/follow up at each centre as determined by 
the treating Investigator, and will continue to be followed in this study until 3 years following 
their initial RAI dose (refer to Section 6.4.6). 
Note that for study purposes the WBS will evaluated by blinded independent central review. If 
local interpretation of WBS scan data indicates uptake suspicious for DTC, any biochemically 
negative patients must still be sent for stage 3 assessments (in case the local and central WBS 
results are discordant).


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Table 5 
Criteria for biochemical decision making (based on standardised central analysis results) 
Stage 1 
Stage 2 
Scenario 
Suppressed Tg 
TgAba 
Stimulated Tg 
TgAba 
Repeat 3rd TgAb 
sampleb 
Biochemical remission? 
1 
 1ng/mL 
Negative 
Not required 
Not required 
Not required 
No. Stop.c 
2 
< 1 ng/mL 
Negative 
< 1 ng/mL 
negative 
Not required 
Yes. Proceed to stage 3 
3 
< 1 ng/mL 
Negative 
 1 ng/mL 
negative 
Not required 
No. Stop.c 
4 
Any 
Positive 
< 1 ng/mL 
negative 
negative 
Yes. Proceed to stage 3 
5 
Any 
Positive 
< 1 ng/mL 
negative 
positive 
No. Stop.c 
6 
< 1 ng/mL 
Negative 
< 1 ng/mL 
positived 
negative 
Yes. Proceed to stage 3 
7 
< 1 ng/mL 
Negative 
< 1 ng/mL 
positive 
positive 
No. Stop.c 
8 
Any 
Positive 
Any 
positive 
Not required 
No. Stop.c 
a Standardised central methodology will be used to define TgAb negative/positive status, refer to Section 6.4.3.4. 
b When the TgAb results from stage 1 and 2 are discordant, a repeat (third) blood sample for TgAb is required 10 days (± 3 days) after the stage 2 blood 
sample. 
c For the purpose of the study, the patient will be deemed not to be in complete remission and no further stage 3 assessments are required. These patients will 
enter standard of care treatment/follow up at each centre as determined by the treating Investigator, and will continue to be followed in this study until 3 
years following their initial RAI dose (refer to Section 6.4.6). 
d Although this stimulated Tg blood sample is positive for TgAb, the patient will be declared to be in biochemical remission if the other two TgAb samples 
are both negative by standardised central analysis. It is not feasible to repeat a second stimulated Tg assessment.


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6.4.2.3 
Primary endpoint assessments Stage 3 
In stage 3, patients with biochemically-negative disease will have: 
x
Neck MRI with gadolinium contrast to be evaluated by blinded independent central 
review. 
x
Chest CT without contrast to be evaluated by blinded independent central review. 
x
If clinically indicated, a biopsy/FNA should be performed as follows: 

For any suspicious lymph nodes on MRI  15 mm in the smallest 
diameter ( 10 mm for level II, III or IV lymph nodes in the neck), or non 
nodal lesions  10 mm in the smallest diameter. 

For any chest abnormalities suspicious on CT  10 mm in the smallest 
diameter should be biopsied/FNA. 
6.4.3 
Blood sample assessments for efficacy 
All protocol-scheduled samples for serum Tg (suppressed and stimulated), TSH and TgAb 
assessment, will be sent for central laboratory analysis using standardised methodology. All 
decision making for study purposes will be based on the standardised central analysis results; 
values obtained from different assay methods may be different and cannot be used 
interchangeably.  
Full details of the sample collection, shipment and analytical methodology is provided in the 
Laboratory Manual. 
Unscheduled samples and local analysis: 
Investigators may also perform local biochemical analysis for these parameters as per standard 
site practice if desired, however this data will not be used for study-related decision making. If 
local analysis is performed, Investigators must ensure that the maximum permissible blood 
volumes for individual patients at their institutions are not exceeded.  
In the case that an investigator performs additional assessment of Tg (and TSH, TgAb) outside 
of the protocol scheduled visits, such samples should not be sent for central laboratory 
analysis. Only if such unscheduled local analysis leads the Investigator to wish to administer 
further therapy for thyroid cancer, should an additional sample ideally be sent for central 
analysis and the protocol-specified re-treatment criteria applied (Section 5.9.1.1) before the 
patient is re-treated.  
6.4.3.1 
Suppressed Tg 
Prior to the 18 month primary endpoint assessments: 
A blood sample for TSH-suppressed serum Tg is required at 9 months after the RAI dose 
(± 3 months) in order to assess whether thyroid cancer re-treatment is clinically indicated; 


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refer to the thyroid cancer re-treatment guidelines in Section 5.9.1.1. Tg assessment for this 
purpose may take place at any time from 6 months after the patient’s RAI treatment (but not 
before 6 months). A second blood sample 2-4 weeks later may also be required to verify the 
biochemical re-treatment criteria (refer to Section 5.9).  
Stage 1 primary endpoint assessments: 
For all patients that have not been re-treated for thyroid cancer prior to the primary endpoint 
assessments 18 months following their RAI dose, a blood sample to centrally analyse the 
TSH-suppressed serum Tg level will be taken. 
Anytime that a Tg blood sample is taken, the same sample will also be centrally analysed for 
TSH and TgAb (refer to Sections 6.4.3.3 and 6.4.3.4 respectively). 
The volume of blood for biochemical assessments is detailed in the Laboratory Manual for 
this study.  
6.4.3.2 
Stimulated Tg 
Prior to the 18 month primary endpoint assessments: 
Prior to the 18 month primary endpoint assessments, stimulated Tg levels are not 
recommended and not included as part of the patient follow up for this study.  
Stage 2 primary endpoint assessments: 
Serum Tg measured during TSH suppression is not sufficiently sensitive to confirm that a 
patient is free of thyroid cancer. For this reason, rhTSH (Thyrogen) stimulated serum Tg level 
will also be assessed at the primary endpoint, only for patients proceeding to stage 2 of the 
primary endpoint assessments. 
For patients that require stimulated Tg assessment, 0.9 mg of rhTSH will be administered IM 
for 2 consecutive days (refer to Section 5.5.4.1), with the blood sample taken for stimulated 
Tg central analysis on day 5. 
The volume of blood for biochemical assessments is detailed in the Laboratory Manual for 
this study.  
Each time that a blood sample is taken for central stimulated Tg analysis, the same sample 
will also be centrally analysed for TgAb (refer to Sections 6.4.3.4 respectively). 
6.4.3.3 
TSH 
Thyroid hormone supplementation will be adjusted in individual patients with the aim of 
achieving suppressed TSH levels of 0.5 mIU/L or less for the duration of the study.  Each time 
that a suppressed Tg sample is taken, TSH should also be assessed (by central standardised 
methodology). 


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The volume of blood for biochemical assessments is detailed in the Laboratory Manual for 
this study.  
6.4.3.4 
Tg antibody (TgAb)  
Each time that a blood sample is taken for central Tg analysis, the same sample will also be 
centrally analysed using standardised methodology for TgAb. Full details of the sample 
collection, shipment and analytical methodology to be used will be provided in the Laboratory 
Manual. 
TgAb cut-off for decision making 
For decision making purposes at any time in the study, standardised central analysis results 
must be used. The cut-off value for positive/negative TgAb status according to the 
standardised central methodology will be provided to sites prior to the start of recruitment. 
At screening: 
Patients with TgAbs present at screening will be ineligible for the study (refer to the exclusion 
criterion in Section 4.2, screening samples must be sent for standardised central analysis). 
Prior to the 18 month primary endpoint assessments: 
If TgAbs are detected in the follow-up Tg blood sample (at 9 months ±3 months), the patient 
should not be re-treated unless new structural disease is detected according to Section 5.9.1.2 
(ie, it is strongly recommended that patients are not re-treated on the basis of new antibodies 
alone, in the absence of structural disease). Refer to Section 5.9. 
Primary endpoint assessments (Stage 1 and 2) 
The TgAb status of the stage 1 blood sample will not be taken into consideration alone. The 
following rules will apply (refer also to Table 5): 
1. 
If both stage 1 and stage 2 blood samples are negative for TgAb, then the Tg results 
will be valid for decision making. 
2. 
If both stage 1 and stage 2 blood samples are positive for TgAb, then the stimulated 
Tg result will be deemed to be uninterpretable, and for the purpose of this study the 
patient will be classified as not in complete remission. No further primary endpoint 
assessments are required.  
3. 
If the stage 1 and 2 blood samples are discordant for TgAb status, then a repeat 
(third) blood sample is required 10 days later (± 3 days). Only if the repeat sample 
is confirmed negative for TgAb, will the stimulated Tg level in stage 2 be 
considered to be interpretable and valid for decision making.   


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6.4.4 
Imaging assessments for efficacy 
6.4.4.1 
Neck ultrasound (US) 
Neck US assessments will take place at the times indicated in the Study Plan Table 3.  Refer 
also to Section 6.4.2 and Table 4 for further details of US assessment at the primary endpoint. 
Any suspicious lymph nodes or lesions in the neck  5 mm in the smallest diameter identified 
by US during the study should be biopsied/FNA. 
Note: for a lesion to be suspicious it must be new or enlarged compared to the previously 
obtained imaging data, and be consistent with the biological characteristics of DTC. 
Biopsy/FNA samples, where performed, will be assessed at each site. Needle washout may be 
analysed locally for Tg according to local standard practice. The totality of the information 
obtained from a biopsy/FNA (including washout Tg data where analysed), will be assessed 
locally to determine presence or absence of thyroid cancer in the sample. 
US definition of structural DTC 
Any soft tissue or lymph node lesions that are new or enlarged compared to previous 
ultrasound assessment (either post operatively and/or at 9 months) that are consistent with the 
biological characteristics of DTC and fulfil the following criteria will be considered as 
structural thyroid cancer: 
x
Lesions of any size confirmed to be structural DTC by positive biopsy/FNA (ie, 
biopsy proven). 
x
Any suspicious lesion or lymph node of any size that is subsequently shown to be 
RAI avid/positive on central review of WBS (in this situation the positive WBS 
data takes precedent over a negative biopsy/FNA from the same lesion/lymph node 
if performed).  
Note, any abnormality on US that is non-RAI avid on the subsequent WBS, will be considered 
benign even in the absence of a biopsy. 
The assessment of neck US and biopsy/FNA sample will be made by investigator site review. 
The local ultrasound information will be recorded in the eCRF (with FNA/biopsy results if 
performed) and provided to the central imaging CRO if necessary as supporting clinical data 
(refer to Section 6.4.4.6).     
Guidelines for standardised acquisition, defining suspicious lesions and reporting of US 
assessments required for this study will be provided to each study site. 


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6.4.4.2 
Whole body diagnostic 131I nuclear medicine scan (WBS) 
Pre-RAI treatment 
There is no pre-ablation WBS in this study. This is a fixed RAI dose study (100mCi, 3.7GBq) 
with Thyrogen stimulation. Study-specific post-operative imaging will be used to ensure that 
enrolled patients do not have overt macronodular disease remaining in the neck or distant 
metastatic disease in the lungs.  
Post-RAI treatment 
All randomised patients will have a WBS performed 3-10 days following their RAI treatment 
dose to assess where the administered 131I has localised. 
It is acknowledged that this assessment may identify a small number of patients with distant 
metastatic disease that was not previously identified (patients with known metastatic disease 
at study entry will be excluded). Such patients will continue in the study and should not be 
withdrawn; they will continue to be followed according to the protocol and will be included in 
both the Intention To Treat (ITT) efficacy and safety analysis sets for the study. 
Primary endpoint (stage 2) 
If required according to Section 6.4.2, the diagnostic WBS to assess the primary endpoint will 
be performed following a diagnostic dose of 5 mCi 131I (refer to Section 5.5.4.2). Patients will 
receive 2 Thyrogen injections on consecutive days (day 1 and 2), followed by a diagnostic 
dose (5 mCi) of 131I on either day 2 or day 3, and a blood draw for stimulated Tg central 
assessment and WBS both on day 5. Patients will be required to adhere to a low iodine diet for 
a period of 1 week before the diagnostic 131I dose, until the diagnostic WBS assessment is 
completed. 
Standardised acquisition and submission guidelines for every WBS procedure will be 
provided separately to this protocol. 
WBS definition of structural DTC 
The WBS evaluation will be made by blinded, independent central review. 
If the central review determines no visible 131I uptake then the WBS for that patient will be 
considered normal/negative (no disease).  Areas considered to be anatomically normal (for 
example uptake in the salivary glands, stomach, gastrointestinal, urinary tract and bladder) 
will not be considered disease. 
If the central review determines there is a low level of visible uptake in the thyroid bed: 
x
Uptake must be < 0.1% to be considered normal/negative (no disease). 
x
If uptake in the thyroid bed region is  0.1%, the patient will be deemed not to be in 
remission due to the presence of iodine-avid DTC. 


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The % uptake in the thyroid bed (using the region-of-interest method drawn over the thyroid 
bed) will be measured and calculated by the local Investigator site and entered into the eCRF, 
to be made available to the central reviewer. 
If an abnormality identified by US  is subsequently shown to be RAI avid on WBS, the WBS 
data takes precedent over a negative biopsy/FNA. 
6.4.4.3 
Neck MRI 
Post-operative (screening) 
This baseline assessment is performed to determine study eligibility according to Section 4.1).  
The baseline post-operative images will be available at the central imaging CRO to aid 
interpretation of the primary endpoint image central read if necessary (refer to Section 6.3). 
Primary endpoint (stage 3) 
Neck MRI to define the primary endpoint will be performed in stage 3 of the assessments in 
patients deemed to be biochemically-negative for thyroid cancer. Refer to Section 6.4.2.3 and 
Figure 3. 
The neck MRI must be performed using T1 weighted image sequences with and without 
gadolinium contrast agent, and T2 weighted image sequences. 
If clinically indicated, any suspicious lymph nodes on MRI  15 mm in the smallest diameter 
( 10 mm for level II, III or IV lymph nodes in the neck), or non nodal lesions  10 mm in the 
smallest diameter, should be biopsied/aspirated by fine needle.  
MRI definition of structural DTC 
New lesions (nodal or non-nodal) or significantly enlarged lymph node lesions compared to 
previous post operative (screening) MRI which are consistent with the biological 
characteristics of DTC and fulfil either of the following criteria will be considered to represent 
structural thyroid cancer: 
x
Lesions of any size confirmed to be structural DTC by positive biopsy/FNA (ie, 
biopsy proven). 
x
Any suspicious lesion or lymph node of any size that is shown to be RAI 
avid/positive on WBS (in this situation the positive WBS data takes precedent over 
a negative biopsy/FNA from the same lesion/lymph node if performed).  
Note, any abnormality on MRI that is non-RAI avid on the WBS, will be considered benign 
even in the absence of a biopsy. 
This assessment will be made by blinded, independent central review. 


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6.4.4.4 
Chest CT 
In this study all chest CT procedures should be performed without iodine containing contrast 
agent. 
Post-operative (screening) 
This baseline assessment is performed to determine study eligibility according to Section 4.1).  
The baseline post-operative images will be available at the central imaging CRO to aid 
interpretation of the primary endpoint image central read if necessary (refer to Section 6.3). 
Primary endpoint (stage 3) 
Chest CT to define the primary endpoint will be performed in stage 3 of the assessments in 
patients deemed to be biochemically-negative for thyroid cancer. Refer to Section 6.4.2.3 and 
Figure 3. 
If clinically indicated, any chest abnormalities suspicious on CT  10 mm in the smallest 
diameter should be biopsied/FNA. 
CT definition of structural DTC 
New lesions (nodal or non-nodal) or significantly enlarged lymph node lesions compared to 
previous post operative (screening) CT which are consistent with the biological characteristics 
of DTC and fulfil either of the following criteria will be considered to represent structural 
thyroid cancer: 
x
Lesions of any size confirmed to be structural DTC by positive biopsy/FNA (ie, 
biopsy proven). 
x
Any suspicious lesion or lymph node of any size that is shown to be RAI 
avid/positive on WBS (in this situation the positive WBS data takes precedent over 
a negative biopsy/FNA from the same lesion/lymph node if performed).  
Note, any abnormality on CT that is non-RAI avid on the WBS, will be considered benign 
even in the absence of a biopsy. 
This assessment will be made by blinded, independent central review  
6.4.4.5 
Biopsy or fine needle aspirate (FNA) 
A biopsy or FNA should be performed in the following situations: 
x
US: For any suspicious lymph nodes or lesions in the neck  5 mm in the smallest 
diameter identified by US during the study. 
x
MRI: If clinically indicated, for lymph nodes suspicious on MRI  15 mm in the 
smallest diameter ( 10 mm for level II, III or IV lymph nodes in the neck), or non 
nodal lesions  10 mm in the smallest diameter. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
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x
CT: If clinically indicated, for any chest abnormalities suspicious on CT  10 mm 
in the smallest diameter. 
Note: for a lesion to be suspicious it must be new or enlarged compared to the previously 
obtained imaging data, and be consistent with the biological characteristics of DTC. 
All biopsy/FNA samples taken during the study will be assessed at each site according to local 
standard practice. Needle washout may be analysed locally for Tg according to local standard 
practice (this is not a mandatory requirement). The totality of the information obtained from a 
biopsy/FNA (including washout Tg data where analysed), will be assessed locally to 
determine presence or absence of thyroid cancer in the sample. This information will be 
provided to the central imaging CRO. 
Refer to Section 6.10.3 for details regarding tumour sample acquisition on disease 
progression. 
6.4.4.6 
Information to be sent to the central imaging CRO 
The following information will be sent to the central imaging CRO (further details are 
provided in the imaging charter/guidelines for this study). 
1. 
Post-operative screening assessments (refer to Section 6.3): images for chest CT 
and neck MRI. This data must be sent for all patients as soon as possible after each 
patient is randomised.  
2. 
Post-RAI WBS images taken 3-10 days after each patient’s RAI dose. This data 
must be sent for all patients as soon as possible after each patient has their post-RAI 
WBS assessment. 
3. 
Primary endpoints assessments stage 1: site ultrasound and biopsy information. The 
required data must be entered into the clinical database for each patient as soon as 
possible after completion of the assessment (NOTE: this information is not sent to 
the central imaging CRO, but instead must be entered into the database directly 
using eCRF). 
4. 
Primary endpoint assessments stage 2: diagnostic WBS images. This data must be 
sent for all patients as soon as possible after completion of the assessment. 
5. 
Primary endpoint assessments stage 3: chest CT and neck MRI images and biopsy 
information (if performed). This data must be sent for all patients as soon as 
possible after completion of the assessments. Biopsy data must be entered into the 
clinical database for each patient as soon as possible after completion of the 
assessment. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
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6.4.5 
Derivation of primary endpoint of complete remission 
The complete remission status of each patient will be determined programmatically by 
AstraZeneca, by incorporating data on re-treatment provided by the site, biochemical data 
from the standardised central laboratory analysis, and structural disease assessment from the 
blinded, independent central review.  
If a patient has received further therapy for thyroid cancer prior to the primary endpoint 
assessment, the patient will be classified as not in complete remission and no further data will 
be considered. 
For patients that have not received further therapy for thyroid cancer, all available imaging 
data will be sent to the imaging CRO.  Determination of presence or absence of structural 
thyroid cancer will be made by the imaging CRO only for biochemically negative patients. A 
list of biochemically negative patients (based on standardised central laboratory analysis) will 
be provided by AstraZeneca to the imaging CRO to enable them to identify which patients to 
assess. 
The imaging CRO will assess the WBS, MRI and CT and also review the site assessment of 
neck US to provide an overall assessment: presence or absence of structural thyroid cancer, or 
not evaluable based on all of the available information. For the derivation of the complete 
remission endpoint, patients that are not evaluable for structural disease assessment will be 
considered as not achieving complete remission, regardless of the result of other assessments.    
AstraZeneca will programmatically combine information on further therapy, biochemical data, 
and the determination of structural disease from the central imaging CRO, to determine the 
complete remission status of each patient as shown in Table 6. 
The dates on which assessments were performed will be incorporated into the derivation of 
the primary endpoint to ensure patients are assessed within a time window around the 
scheduled 18 month post-RAI treatment. The first assessment must be started at 18 months 
± 2 weeks following the patient’s RAI dose, and all necessary primary endpoint assessments 
must be completed within a 8 week period. If a patient has assessments/scans that fall outside 
of these time windows, the patient will be considered not to be in complete remission, 
regardless of the assessment of disease status. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
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Table 6 
Programmatic derivation of complete remission status 
Biochemical datab 
Scenario 
Further 
thyroid cancer 
therapya       
(re-treatment) 
Stimulated Tgb 
TgAbb 
Structural 
disease 
assessmentc 
Complete 
remission 
1 
Yes 
N/A 
N/A 
N/A 
No 
2 
No 
< 1 ng/mL 
Negatived 
Absence of 
disease 
Yes 
3 
No 
 1ng/mL 
Any 
Any 
No 
4 
No 
Any 
Positived 
Any 
No 
5 
No 
Any 
Any 
Presence of 
disease 
No 
6 
No 
NE 
Any 
Any 
No 
7 
No 
Any 
NE 
Any 
No 
8 
No 
Any 
Any 
NE 
No 
a As assessed by investigator at site. 
b As assessed by standardised central laboratory analysis. 
c As assessed by blinded, independent central review. 
d  If the stage 1 and 2 blood samples are discordant for TgAb status, then a third blood sample 10 days later (± 3 days) is required. Only if the third sample is 
negative for TgAb will the overall TgAb result be considered negative for the primary endpoint assessments. Refer also to Table 5. 
N/A primary endpoint assessments are not required for patients that have received further treatment for thyroid cancer in the previous 18 months. 
NE Not evaluable (for example due to missing samples or assessments). 
 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
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6.4.6 
Clinical remission 
The secondary efficacy endpoint for this study is clinical remission rate at 18 months 
(following RAI treatment). This is designed to more typically reflect clinical practice. As 
such, the definition of clinical remission will exclude the additional radiological assessments 
performed for the purpose of complete remission in this study. 
Definition of clinical remission: 
Patients will be defined to be in clinical remission if all of the following criteria can be 
demonstrated: 
1. 
Serum Tg levels < 1ng/mL during rhTSH stimulation, in the absence of interfering 
Tg antibodies, as assessed by standardised central laboratory analysis. 
2. 
No confirmed evidence of thyroid cancer on neck US, as assessed by investigator 
site review. 
3. 
No evidence of thyroid cancer on diagnostic WBS, as assessed by blinded 
independent central review.  
4. 
No histopathological evidence of thyroid cancer on FNA/biopsy when performed to 
clarify equivocal US findings, as assessed by investigator site review. 
5. 
No further thyroid cancer therapy was administered in the first 18 months following 
the initial RAI treatment.  
6.4.7 
Derivation of clinical remission status 
The clinical remission status of each patient will be determined programmatically by 
AstraZeneca, by incorporating data on re-treatment provided by the site, biochemical data 
from the standardised central laboratory analysis, structural disease assessment based on US 
by investigator site review and structural disease assessment based on WBS from the blinded, 
independent central review.  
If a patient has received further therapy for thyroid cancer prior to the primary endpoint 
assessment, the patient will be classified as not in clinical remission and no further data will 
be considered. 
For patients that have not received further therapy for thyroid cancer: 
A determination of presence or absence of structural thyroid cancer or not evaluable will be 
made by the investigator based on US.  
A determination of presence or absence of structural thyroid cancer or not evaluable will be 
made by the central imaging CRO based on WBS for only biochemically negative patients. 
Information on US will not be reviewed as part of this assessment. A list of biochemically 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
85(118) 
negative patients (based on standardised central laboratory analysis) will be provided by 
AstraZeneca to the imaging CRO to enable them to identify which patients to assess. 
AstraZeneca will programmatically combine information on further therapy, biochemical data, 
determination of structural disease from the investigator site assessment of US and 
determination of structural disease from the central imaging CRO of WBS, to determine the 
clinical remission status of each patient.  
Full details of the programmatic derivation of clinical remission will be provided in the SAP. 
6.4.8 
Final study follow up at 3 years 
The final study follow-up will take place 3 years post-RAI for each patient, and will include: 
1. 
The clinical status of each patient, for example: remission, persistent disease, 
recurrent disease, survival status. 
2. 
The incidence of further therapy (re-treatment) for thyroid cancer, for example, 
additional RAI or surgery. 
3. 
Final assessment of selumetinib or RAI-related AEs and SAEs. 
Note, following the primary endpoint assessments until the final study visit at 3 years 
following each patient’s initial RAI treatment, each patient will enter standard of care 
treatment or follow up according to local practice. No study-specific assessments will be 
performed, and locally performed assessments and data will not typically be collected as 
routine in the clinical study database (except for safety data, refer to Section 6.5.3). The 
patient’s clinical status at the final study follow up will be collected (along with any relevant 
supporting local assessment data). For example, remission status will be defined by the 
Investigator on the eCRF based on the relevant local standard of care assessments (eg, locally 
assessed Tg and no evidence of thyroid cancer on locally assessed US). 
6.5 
Safety 
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. 
6.5.1 
Definition of adverse events  
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition 
can be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the 
abnormal results of an investigation (eg, laboratory findings, electrocardiogram).  In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered. 
The term AE is used to include both serious and non-serious AEs. 


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6.5.2 
Definitions of serious adverse event 
A serious adverse event is an AE occurring during any study phase (ie, run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria: 
x
Results in death 
x
Is immediately life-threatening 
x
Requires in-patient hospitalisation or prolongation of existing hospitalisation  
x
Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions 
x
Is a congenital abnormality or birth defect 
x
Is an important medical event that may jeopardise the patient or may require 
medical intervention to prevent one of the outcomes listed above 
For further guidance on the definition of a SAE, see Appendix B to the Clinical Study 
Protocol. 
6.5.3 
Recording of adverse events 
All adverse events will be graded according to NCI CTCAE Version 4. 
Time period for collection of adverse events 
All AEs/SAEs will be collected from informed consent until 30 days following the last dose of 
study treatment (selumetinib or placebo).  
After this time: 

all SAEs regardless of causality will be collected until the final study 
follow-up (3 years post-RAI for each patient, refer to Section 6.4.8) 

only AEs considered causal to RAI or the combination of RAI and study 
treatment will be collected until the final study follow-up (3 years post-
RAI for each patient, refer to Section 6.4.8). 
Follow-up of unresolved adverse events 
Any AE or laboratory change occurring during the study treatment period should be followed 
up by the investigator for as long as medically indicated (resolution or stabilisation), and 
follow up information  recorded in the eCRF. 
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the CRF. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
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AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
Variables 
The following variables will be collected for each AE: 
x
AE (verbatim) 
x
The date when the AE started and stopped 
x
CTCAE grade information 
x
Whether the AE is serious or not 
x
Investigator causality rating against the Investigational Product (yes or no) and/or 
RAI (yes or no) 
x
Action taken with regard to investigational product 
x
AE caused patient’s withdrawal from study treatment 
x
Treatments patient received for AE 
x
Outcome 
x
Whether event constitutes an SAE. 
In addition, the following variables will be collected for SAEs: 
x
Date AE met criteria for serious AE 
x
Date Investigator became aware of serious AE 
x
AE is serious due to 
x
Date of hospitalisation 
x
Date of discharge 
x
Probable cause of death (if applicable) 
x
Date of death (if applicable) 
x
Autopsy performed (if applicable) 
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.5.2.  An AE of severe 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
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intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE. On the other hand, a stroke 
that results in only a limited degree of disability may be considered a mild stroke but would be 
a SAE. 
Causality collection 
The Investigator will assess causal relationship between Investigational Product and RAI and 
each Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’ 
For SAEs causal relationship will also be assessed for other medication, study procedures and 
additional study drug (eg, RAI).  Note that for SAEs that could be associated with any study 
procedure the causal relationship is implied as ‘yes.’ 
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol. 
Adverse Events based on signs and symptoms 
All AEs spontaneously reported by the patient, or reported in response to the open question 
from the study personnel: ‘Have you had any health problems since the previous visit/you 
were last asked?’ or revealed by observation, will be collected and recorded in the CRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately. 
Adverse Events based on examinations and tests 
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
clinical study report.  Deterioration as compared to baseline in protocol-mandated laboratory 
values, vital signs etc should therefore only be reported as AEs if they fulfil any of the SAE 
criteria or are the reason for discontinuation of treatment with the investigational product. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s). 
After the 30 day follow up visit, AEs associated with RAI or the combination of study 
treatment and RAI, should continue to be collected by AE reporting, these would include 
abnormalities, for example, white blood cell count or Hb reductions.  
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
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Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
Cases where a patient shows an AST or ALT 3xULN or total bilirubin  2xULN may need 
to be reported as SAEs, please refer to Appendix D ‘Actions required in cases of combined 
increase of aminotransferase and total bilirubin – Hy’s Law,’ for further instructions. All 
patients with an AST, ALT or bilirubin value above ULN at time of the last dose of 
selumetinib/placebo should have a further liver chemistry profile (AST, ALT, bilirubin and 
ALP) performed 30 days (± 7 days) later for follow-up. 
6.5.3.1 
Disease progression 
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the investigational product is being studied.  It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease.  Events, 
which are unequivocally due to disease progression, should not be reported as an AE during 
the study. 
6.5.4 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the CRF. 
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
appropriate AstraZeneca representatives immediately, or no later than 24 hours of when he 
or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within one 
calendar day of initial receipt for fatal and life threatening events and within five calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative. 
If the WBDC system is not available, then the Investigator or other study site personnel 
reports a SAE to the appropriate AstraZeneca representative by telephone. 
The AstraZeneca representative will advise the Investigator/study site personnel how to 
proceed. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
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The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug. 
6.5.5 
Laboratory safety assessment 
Blood and urine samples for determination of clinical chemistry, haematology and urinalysis 
will be taken at the times indicated in the Study Plan (Table 3). For samples taken after Day 1 
during the study treatment period, the sample may be taken any time of day (ie, it does not 
matter whether it is pre-dose or post-dose). Day 1 samples should be taken pre-dose. 
The following laboratory variables will be measured: 
Table 7 
Laboratory safety assessments 
Clinical chemistry 
Haematology 
Urinalysis a 
s-Albumin 
Erythrocyte count 
u-Albumin 
s-ALT 
Haemoglobin 
u-Creatinine 
s-AST 
Platelet count 
 
s-ALP 
Leucocyte cell count 
 
s-Total Calcium 
Leucocyte differential count (absolute count): 
 
s-Creatinine 
Neutrophils 
 
s-Gamma glutamyl transferase (JGT) 
Eosinophils 
 
s-Glucose 
Basophils 
 
s-Magnesium 
Lymphocytes 
 
s-Phosphate 
Monocytes 
 
s-Potassium 
 
 
s-Sodium 
 
 
s-Total protein 
 
 
s-Total bilirubin 
 
 
s-Urea nitrogen 
 
 
s-Creatine kinase 
 
 
a A single-spot urine specimen will be collected on the day of scheduled visit, at sites where the local laboratory 
is able to determine the concentration of urine albumin and urine creatinine from a single-spot urine specimen.  
Investigational sites unable to report these parameters will perform routine urinalysis according to the local 
standard of care.  
s serum 
u urine  
 
All laboratory safety assessments will be analysed by the local laboratory. 
Clinical chemistry, haematology and urinalysis testing will be repeated as clinically indicated 
as part of the routine management of the patient on the occurrence of AEs. 
For blood volume see Table 9. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
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Date 3rd April 2013 
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6.5.6 
Physical examination 
A complete physical examination will be performed at the times indicated in the Study Plan 
Table 3. 
6.5.7 
Cardiac monitoring 
Note: troponin assessment in this study is only required for cardiac AE follow up as clinically 
indicated. 
6.5.7.1 
ECHO or MUGA 
An ECHO or MUGA assessment (according to site preference) will be conducted at the 
timepoints indicated in the Study Plan (Table 3). A further assessment should be performed as 
part of the assessment package for any cardiorespiratory adverse event with no obvious 
diagnosis.  Medical management of the event should follow local clinical practice.  
Selumetinib interruption should be considered until resolution of the event or until return to 
baseline. 
LVEF can be measured in many different ways but echography is the preferred choice when 
possible.  The same modality should be used as baseline for any ECHO/MUGA follow up. 
Recommendations include  having complete high quality standardized 2-D with Doppler 
echocardiographic examinations performed by an experienced sonographer (preferably with 
the same operator performing all studies for a given patient), according to a specified protocol 
including evaluation of both systolic and diastolic left ventricular function.  Ejection fraction 
determinations should be assessed quantitatively based on bi-plane measurements of end 
diastolic and end systolic left ventricular volumes. 
6.5.7.2 
Resting 12-lead ECG 
ECGs will be analysed locally at each site.  Patients should be supine and at rest 10 minutes 
prior to recording the ECG. 
Parameters including heart rate, duration of QRS complex, PR and QT intervals will be 
collected.  R-R interval and QTcF will be calculated by AstraZeneca from the data provided. 
The investigator should review the paper copy of the ECGs on each study day and may refer 
to a local cardiologist if appropriate. 
Any symptoms from the patient should be registered as a comment and if AE criteria are met, 
recorded as an AE. 
At screening all patients will have a single 12-lead ECG performed.  The screening ECG can 
be conducted up to 28 days prior to randomisation. 
During the treatment phase of the study, patients will have single 12-lead ECGs assessments 
at the following timepoints: 
x
1-2 hours after the first dose of study treatment on Day 1 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
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x
1-2 hours after the first dose of study treatment on Day 29 or 30 
x
At the 30-day follow up visit following completion of study treatment   
x
Single ECGs must also be performed at the time of any ECHO/MUGA assessment, 
and on occurrence of any cardiorespiratory adverse event   
x
A single 12-lead ECG is also required at premature discontinuation of treatment 
6.5.8 
Vital signs 
Resting blood pressure and pulse rate will be measured using a semi-automatic blood pressure 
recording device with an appropriate cuff size.  Vital sign assessments, including weight, will 
be performed at the times indicated in the Study Plan Table 3. Pulse and blood pressure must 
also be performed at the time of any ECHO/MUGA assessment, and on occurrence of any 
cardiorespiratory adverse event.  Height will be assessed at Visit 1 only.   
Any changes in vital signs should be recorded as an AE if applicable. 
6.5.9 
Other safety assessments 
6.5.9.1 
Pregnancy test 
A serum or urine pregnancy test (according to local practice) will be performed at the times 
indicated in the Study Plan Table 3. Following the RAI treatment, monitoring for pregnancy 
will be performed according to standard clinical practice at each centre. 
6.5.9.2 
Ophthalmologic examination 
An ophthalmologic examination (best corrected visual acuity, intraocular pressure, slit lamp 
fundoscopy) should be performed at the timepoints indicated in the Study Plan (Table 3), and 
if a patient experiences a visual symptoms (including blurring of vision) with additional tests 
if clinically indicated e.g. consider OCT scans. 
Patients who have a retinal abnormality prior to discontinuation of selumetinib/placebo should 
have a follow up eye examination performed within 30 days after discontinuation of 
selumetinib/placebo in order to document reversibility. 
An algorithm for management and investigation of visual symptoms is provided in 
Appendix G: “Guidance for Management of Adverse Events in Studies of Selumetinib.” 
6.6 
Patient reported outcomes (PRO) – not applicable 
Patient reported outcomes will not be collected in this study. 


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Study Code D1532C00065 
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Date 3rd April 2013 
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6.7 
Pharmacokinetics  
6.7.1 
PK samples required 
Blood samples (2 mL) for determination of plasma concentrations of selumetinib and 
N-desmethyl selumetinib will be collected from every patient according to the time points 
below.  Other metabolites (eg, selumetinib amide) may also be determined in the PK analysis. 
Each patient will be asked to contribute 8 blood samples, one from each of the pre defined 
time windows below on both Day 1 and Day 29 or Day 30.  The Day 29 or Day 30 PK blood 
samples may be taken earlier, from Day 22 onwards of study treatment if preferred, but it is 
essential that all PK blood samples are collected on a visit day prior to the RAI dose being 
administered.  
x
Pre-dose (within 15 minutes of dosing) 
x
Between 15 minutes and 1 hour post-dose 
x
Between 1.5 and 2.5 hours post-dose 
x
Between 3 and 8 hours post-dose 
Depending on emerging data/information, the timings and number of the PK samples may be 
altered, but the maximum total blood volumes given in Table 9 will not be exceeded.  The 
actual sample date and time of all PK samples must be recorded in the eCRF. 
Samples will be collected, labelled, stored and shipped as detailed in Laboratory Manual.  
6.7.2 
Determination of drug concentration 
Samples for determination of selumetinib and N-desmethyl selumetinib concentrations in 
plasma will be analysed by Covance on behalf of Clinical Bioanalysis Alliance, AstraZeneca 
R&D, using an appropriate bioanalytical method. Other metabolites (eg, selumetinib amide) 
may also be determined in the PK analysis. Full details of the bioanalytical method used will 
be described in a separate bioanalytical report. 
For each placebo patient, samples will only be analysed on a ‘for cause’ basis, for example, if 
no quantifiable concentrations were observed in a patient’s samples when the drug was 
expected to be present. 
All samples still within the known stability of the analytes of interest (ie, selumetinib, N-
desmethyl selumetinib and its metabolites) at the time of receipt by the bioanalytical 
laboratory will be analysed. 
6.8 
Pharmacodynamics – not applicable 
Pharmacodynamic samples will not be taken during this study.  


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6.9 
Pharmacogenetics 
6.9.1 
Genetic blood sample at study entry 
An optional blood sample for genetic research will be obtained from eligible patients at Visit 1 
or 2 ideally.  If for any reason the sample is not drawn at Visit 1 or 2, it may be taken at any 
visit before the RAI dose is administered (radioactive samples for this purpose will not be 
accepted).  Although genotype is a stable parameter, early sample collection is preferred to 
avoid introducing bias through excluding patients who may withdraw due to an adverse event 
(AE), such patients would be important to include in any genetic analysis.  Only one sample 
should be collected per patient for this purpose.  Samples will be collected, labelled, stored 
and shipped as detailed in the Laboratory Manual. 
For blood volumes see Section 7.1. 
6.10 
Biomarker analysis 
6.10.1 
BRAF and NRAS patient population 
Archival tumour sample from every patient will be analysed for BRAF and NRAS mutational 
status centrally using standardised methodology. Full analytical methodology details will be 
provided in the CSR. 
The genetic analysis of archival tumour samples to identify the BRAF and NRAS patient 
population will be performed retrospectively in the study (after randomisation but prior to the 
primary endpoint data analysis). 
BRAF/NRAS positive = mutations in BRAF/NRAS have been detected 
BRAF/NRAS negative =  no mutation in BRAF/NRAS has been detected   
BRAF/NRAS unknown = mutation status in BRAF/NRAS cannot be confirmed 
6.10.1.1 Archival tumour sample 
All patients will be required to provide consent for AstraZeneca to collect and analyse 
samples of their previously obtained tumour material (ie, from their recent surgery) for 
analysis of biomarkers relevant to DTC. Archival tumour sample provision is mandatory in 
this study, and each Investigator should make every effort to collect a sample from all 
randomised patients.  It is accepted that it may not be possible to obtain all samples prior to 
commencement of study treatment (which should continue as planned).  However, it should be 
established during the screening period that sufficient sample exists and is available. Samples 
are expected to be made available as soon as possible. Note, no replacements will be made for 
patients where an archival tumour sample is not provided. 
These samples will be analysed for the biomarkers necessary for the definition of the second 
primary objective patient population (BRAF and NRAS mutational status), and may also be 
used for exploratory analyses on residual material. Such analyses may include (but are not 
restricted to): 


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x
Mutational status of BRAF and NRAS genes, RET rearrangements, and other known 
MAPK and PI3K effector oncogenes.  
x
Baseline expression of pathway and thyroid differentiation specific genes such as 
NIS, Tg, TPO, and PAX8. 
x
Comprehensive genetic analysis to ensure coverage of the major mutational events 
in DTC. 
The exploratory analyses from tumour material may include but are not limited to mRNA 
expression profiling, microRNA expression profiling, gene copy number analysis and protein 
expression by immunohistochemistry for any markers relevant to DTC, either known at the 
time of analysis, or identified in the future. 
For the tumour samples detailed below, each site will be asked to provide one of the following 
for each randomised patient: 

Formalin-fixed, paraffin-embedded tumour tissue block, 
or 

20 pre-cut sections from formalin-fixed paraffin-embedded tumour tissue 
block, presented on slides. Each section is to be 5 ȝm thick.  
Sites should ship the tumour sample as soon as it is available.  If mutational status cannot be 
adequately determined from the initial tumour biopsy sample, and histopathological review 
shows it to be a poor quality sample, a second sample should be submitted for re-testing.   
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual. 
If requested, unused tumour samples will be repatriated.  For further details see the Laboratory 
Manual. 
6.10.2 
Collection of plasma and serum for exploratory biomarker research 
All randomised patients will be required to provide a blood sample at or before randomisation, 
and disease progression (for example, when the patient is re-treated for persistent or recurrent 
thyroid cancer) for exploratory biomarker research. 
All patients will be required to provide: 

1x 10ml blood sample for preparation of serum at randomisation (any 
time before the first dose of study treatment for eligible patients) and 
disease progression. 


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
1x 10ml blood sample for preparation of plasma at randomisation (any 
time before the first dose of study treatment for eligible patients) and 
disease progression. 
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual. 
Residual material may be used for exploratory biomarker research. 
6.10.3 
Collection of disease progression tumour sample 
Patients will be asked to provide a tumour sample removed during the study when the patient's 
cancer is deemed to have progressed (for example, when the patient is re-treated for persistent 
or recurrent thyroid cancer, or has had further surgery). This is an optional sample. 
This will enable a comparison to be made of (for example) tumour genetics and relevant 
signal transduction pathways between the randomisation and the disease progression tumour 
sample and also the evolution of the tumour biology in response to treatment with selumetinib 
can be explored. Such changes may reflect an evolution in phenotype of the tumour, which 
ultimately may guide future treatment decisions post progression on selumetinib. 
Samples can be of any type (such as FNA, or tumour sample taken from a surgical procedure 
performed as part of the patient’s disease management plan), and will be collected, labelled, 
stored and shipped as detailed in the Laboratory Manual. 


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Table 8 
Biomarker summary table 
Biomarker sample 
Time point 
Protocol Section 
Archival tumour for NRAS and BRAF 
analysisa 
Randomisation 
6.10.1.1 
Plasma sample for exploratory biomarker 
analysis 
Randomisation and disease 
progression 
6.10.2 
Serum sample for exploratory biomarker 
analysis 
Randomisation and disease 
progression 
6.10.2 
Disease progression tumour biopsy 
(optional) 
Disease progression 
6.10.3 
Blood sample for genetic analysis 
(optional) 
Randomisation 
6.9.1 
a Residual tissue sample material will be stored for potential retrospective biomarker analysis, which will be 
performed in an AstraZeneca laboratory or AstraZeneca approved laboratory. 
7. 
BIOLOGICAL SAMPLING PROCEDURES  
7.1 
Volume of blood 
The total volume of blood (maximum) that will be drawn from each patient in this study is as 
follows: 
Table 9 
Volume of blood to be drawn from each patient  
Assessment 
Maximum 
sample 
volume a 
(mL) 
Typical 
number of 
samples (over 
18+ months) 
Total volume 
(mL) 
Safety 
Clinical chemistry (local analysis) 
5 
5 
25 
 
Haematology (local analysis) 
3 
7 
21 
Efficacy 
Tg, TSH, TgAb (central analysis) 
10 
4 
40 
PK 
2 
8 
16 
Genetics at randomisation (optional) 
10 
1 
10 
Exploratory biomarkers at randomisation, serum  
10 
1 
10 
Exploratory biomarkers at randomisation, plasma  
10 
1 
10 
Exploratory biomarkers on progression, serum  
10 
1 
10 
Exploratory biomarkers on progression, plasma  
10 
1 
10 
Total 
 
 
152 
a All volumes presented are maximums. The actual volume requirements will be detailed in the Laboratory Manual. 


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7.2 
Handling, storage and destruction of biological samples 
Biological samples for future research may be retained at or on behalf of AstraZeneca for a 
maximum of 25 years following the Last Patient’s Last Visit in the study.  The results from 
future analysis will not be reported in the Clinical Study Report but separately in a Scientific 
Report or Scientific Publication. 
7.2.1 
Pharmacokinetic samples 
Samples will be anonymised by pooling or will be disposed of after the Bioanalytical report 
finalisation or six months after issuance of the draft Bioanalytical report (whichever is earlier), 
unless requested for future analyses. Pooled, anonymised samples may be used for analytical 
method development and/or validation. Anonymised samples will be retained for no more 
than 5 years after the CSR is finalised. Samples may also be disposed of earlier, pending 
further notification. 
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation will not be reported in the Clinical Study 
Report but separately in a Bioanalytical report. 
7.2.2 
Pharmacogenetic samples 
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality.  Samples will be stored for a maximum of 25 
years, from the date of the Last Patient’s Last Visit, after which they will be destroyed.  DNA 
is a finite resource that may be used up during analyses.  Samples will be stored and used until 
no further analyses are possible or the maximum storage time has been reached. 
For all samples irrespective of the type of coding used the DNA will be extracted from the 
blood sample.  The DNA sample will be assigned a unique number replacing the information 
on the sample tube. Thereafter, the DNA sample will be identifiable by the unique DNA 
number only.  The DNA number is used to identify the sample and corresponding data at the 
AstraZeneca genetics laboratories, or at the designated contract laboratory.  No personal 
details identifying the individual will be available to any person (AstraZeneca employee or 
contract laboratory staff working with the DNA.) 
The samples and data for genetic analysis in this study will be single coded.  The link between 
the patient enrolment/randomisation code and the DNA number will be maintained and stored 
in a secure environment, with restricted access WITHIN the Clinical Genotyping Group 
Laboratory Information Management System (LIMS) at AstraZeneca.  The link will be used 
to identify the relevant DNA samples for analysis, facilitate correlation of genotypic results 
with clinical data, allow regulatory audit and to trace samples for destruction in the case of 
withdrawal of consent when the patient has requested disposal/destruction of collected 
samples not yet analysed.  


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7.3 
Labelling and shipment of biohazard samples 
The Principal Investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria), 
see Appendix C ‘IATA 6.2 Guidance Document.’ 
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the patient unless agreed with AstraZeneca and appropriate 
labelling, shipment and containment provisions are approved. 
7.4 
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle. 
The Principal Investigator at each centre keeps full traceability of collected biological samples 
from the patients while in storage at the centre until shipment or disposal (where appropriate) 
and keeps documentation of receipt of arrival. 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival. 
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers. 
Samples retained for further use are registered in the AstraZeneca biobank system during the 
entire life cycle. 
7.5 
Withdrawal of informed consent for donated biological samples 
If a patient withdraws consent to the use of any optional donated biological samples, the 
samples will be disposed of/destroyed, and the action documented.  If samples are already 
analysed, AstraZeneca is not obliged to destroy the results of this research. 
The Principal Investigator: 
x
Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca 
x
Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented 
x
Ensures the laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed/destroyed, the action 
documented and the signed document returned to the study site 
x
Ensures that the patient and AstraZeneca are informed about the sample disposal. 


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AstraZeneca ensures the central and bioanalytical laboratories holding the samples are 
informed about the withdrawn consent immediately and that samples are disposed 
of/destroyed and the action documented and returned to the study site. 
8. 
ETHICAL AND REGULATORY REQUIREMENTS 
8.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples. 
8.2 
Patient data protection 
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation. 
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician or any other third party, unless 
required to do so by law. 
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an investigator might know a patient’s 
identity and also have access to his or her genetic data. Also Regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate. 
8.3 
Ethics and regulatory review 
An Ethics Committee should approve the final study protocol, including the final version of 
the Informed Consent Form and any other written information and/or materials to be provided 
to the patients.  The investigator will ensure the distribution of these documents to the 
applicable Ethics Committee, and to the study site staff. 
The opinion of the Ethics Committee should be given in writing. The investigator should 
submit the written approval to AstraZeneca before enrolment of any patient into the study.  
The Ethics Committee should approve all advertising used to recruit patients for the study. 
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements. 


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If required by local regulations, the protocol should be re-approved by the Ethics Committee 
annually. 
Before enrolment of any patient into the study, the final study protocol, including the final 
version of the Informed Consent Form, is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations. 
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities. 
AstraZeneca will provide Regulatory Authorities, Ethics Committees and Principal 
Investigators with safety updates/reports according to local requirements, including SUSARs 
(Suspected Unexpected Serious Adverse Reactions), where relevant. 
In the USA the Principal Investigator is also responsible for providing the Ethics Committee 
with reports of any serious and unexpected adverse drug reactions from any other study 
conducted with the investigational product.  AstraZeneca will provide this information to the 
Principal Investigator. 
Progress reports and notifications of serious and unexpected adverse drug reactions will be 
provided to the Ethics Committee according to local regulations and guidelines. 
8.4 
Informed consent 
The Principal Investigator(s) at each centre will: 
x
Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study 
x
Ensure each patient is notified that they are free to discontinue from the study at any 
time 
x
Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided 
x
Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study 
x
Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File 
x
Ensure a copy of the signed Informed Consent Form is given to the patient 
x
Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the informed consent form that is approved by an Ethics Committee 


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8.5 
Changes to the protocol and informed consent form 
Study procedures will not be changed without the mutual agreement of the International co-
ordinating Investigator and AstraZeneca. 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol). 
The amendment is to be approved by the relevant Ethics Committee and if applicable, also the 
national regulatory authority approval, before implementation.  Local requirements are to be 
followed for revised protocols. 
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s). For distribution to Ethics Committee see Section 8.3. 
If a protocol amendment requires a change to a centre’s Informed Consent Form, AstraZeneca 
and the centre’s Ethics Committee are to approve the revised Informed Consent Form before 
the revised form is used.  
If local regulations require, any administrative change will be communicated to or approved 
by each Ethics Committee. 
8.6 
Audits and inspections 
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification.  The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analysed, and accurately reported according to the protocol, Good Clinical 
Practice (GCP), guidelines of the International Conference on Harmonisation (ICH), and any 
applicable regulatory requirements.  The investigator will contact AstraZeneca immediately if 
contacted by a regulatory agency about an inspection at the centre. 
9. 
STUDY MANAGEMENT BY ASTRAZENECA 
9.1 
Pre-study activities 
Before the first patient is entered into the study, it is necessary for a representative of 
AstraZeneca to visit the investigational study site to: 
x
Determine the adequacy of the facilities 
x
Determine availability of appropriate patients for the study 
x
Discuss with the investigator(s) (and other personnel involved with the study) their 
responsibilities with regard to protocol adherence, and the responsibilities of 


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AstraZeneca or its representatives.  This will be documented in a Clinical Study 
Agreement between AstraZeneca and the investigator. 
9.2 
Training of study site personnel 
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and the WBDC 
system(s) utilised. 
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. 
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff). 
9.3 
Monitoring of the study 
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to: 
x
Provide information and support to the investigator(s) 
x
Confirm that facilities remain acceptable 
x
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the CRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks 
are being performed 
x
Perform source data verification (a comparison of the data in the CRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent of participating patients. This 
will require direct access to all original records for each patient (eg, clinic charts) 
x
Ensure withdrawal of informed consent to the use of the patient’s biological 
samples is reported and biological samples are identified and disposed of/destroyed 
accordingly, and the action is documented, and reported to the patient 
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct. 
9.3.1 
Source data 
Refer to the Clinical Study Agreement for location of source data. 


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9.4 
Study agreements 
The Principal Investigator at each/the centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of patients and in all other respects, not relating to study conduct or treatment of 
patients, the terms of the Clinical Study Agreement shall prevail. 
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled. 
9.4.1 
Archiving of study documents 
The Investigator follows the principles outlined in the Clinical Study Agreement (CSA). 
9.5 
Study timetable and end of study 
The end of the study is defined as ‘the last visit of the last patient undergoing the study.’ All 
patients in this study will be followed for 3 years following their RAI treatment. 
The study is expected to start in 2013 and to end in 2017. 
The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or if recruitment is slow.  AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with selumetinib. 
10. 
DATA MANAGEMENT BY ASTRAZENECA OR DELEGATE 
Data entered in the WBDC system will be immediately saved to a central database and 
changes tracked to provide an audit trail. When the principal investigator has signed the eCRF 
electronically as per eCRF instructions, the subject’s data will be locked. 
Medical coding will be performed using the AstraZeneca Autocoder application.  The Data 
Management Centre Coding Team will perform coding using agreed coding conventions.  
AEs and medical and surgical history will be coded using the standard dictionary – Medical 
Dictionary for Regulatory Activities (MedDRA), and concomitant medication will be coded 
using the AstraZeneca Drug Dictionary. 
SAEs will be entered into a global patient safety database for regulatory reporting purposes 
and be reconciled with the AEs in the clinical database. 
Data associated with biological samples will be transferred to the data manager as an 
electronic file and merged with study data as appropriate. 


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Data from external providers (eg, central laboratory) will be validated as appropriate to ensure 
that it is consistent with the clinical data and included in the final database. 
Clean file will be declared for the database once all data have been received, entered, 
validated and all queries resolved.  The database will be locked after clean file has been 
declared.  Treatment codes will not be broken until after clean file.  Following database lock, 
all data will be extracted as SAS (Statistical Analysis Software) data sets for the statistical 
analysis to be performed by AstraZeneca.  
Any genotype data generated in this study will be stored in the AstraZeneca genotyping LIMS 
database, or other appropriate secure system within AstraZeneca and/or third party contracted 
to work with AstraZeneca to analyse samples.  The results from this genetic research may be 
reported in the CSR for the main study, or in a separate report as appropriate. Some or all of 
the clinical datasets from the main study may be merged with the genetic data in a suitable 
secure environment separate from the clinical database.  The results from this genetic research 
will be reported separately from the Clinical Study Report for the main study. 
11. 
EVALUATION AND CALCULATION OF VARIABLES BY 
ASTRAZENECA OR DELEGATE 
11.1 
Calculation or derivation of efficacy variable(s) 
11.1.1 
Complete remission rate at 18 months post-RAI treatment 
Patients will be considered to be in complete remission if they are alive and all of the criteria 
in Section 6.4.1 are met at 18 months post-RAI treatment. 
Complete remission rate at 18 months post-RAI treatment is defined as the proportion of 
patients who have achieved complete remission at this time point. The complete remission 
rate will be calculated using all randomized patients as the denominator.  
11.1.2 
Clinical remission rate at 18 months post-RAI treatment 
Patients will be considered to be in clinical remission if they are alive and all of the criteria in 
Section 6.4.6 are met at 18 months post-RAI treatment. 
Clinical remission rate at 18 months post-RAI treatment is defined as the proportion of 
patients who have achieved clinical remission at this time point. The clinical remission rate 
will be calculated using all randomized patients as the denominator. 
11.1.3 
Thyroid cancer recurrence 
The occurrence and date of any thyroid cancer recurrence will be recorded for patients who 
have previously entered either complete or clinical remission (at any point during the study or 
follow up periods). The rate of thyroid cancer recurrence will be calculated using only patients 
who have achieved remission as the denominator. 


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11.1.4 
Survival status 
The survival status and survival assessment date of all patients will be recorded. Survival time 
will be calculated as the time from the date of randomisation to the date of death. Patients who 
have not died at the time of the final study follow up will be censored at the last date the 
patient was known to be alive. 
11.1.5 
Further therapy 
The dates and type of any further therapy for thyroid cancer will be recorded during the study 
and follow up periods. 
11.2 
Calculation or derivation of safety variable(s) 
11.2.1 
Adverse events 
Adverse events will be listed for each patient and summarised by treatment received according 
to the System Organ Class (SOC) and preferred term assigned to the event using the 
MedDRA.  AEs will be graded according to the National Cancer Institute Common 
Terminology Criteria for AEs Version 4.  The CTC Grade will be assigned by the 
Investigator. 
AE summaries will include all of the following: 
x
Any AEs occurring after commencement of study treatment and within 30 days of 
the last dose of study medication 
x
AEs related to RAI or the combination of RAI and study treatment occurring 
between 30 days after the last dose of study medication and the final study visit at 3 
years following the initial RAI dose 
x
All SAEs occurring after commencement of study treatment until the final study 
visit at 3 years following the initial RAI dose 
AEs occurring before commencement of study treatment will not be included in AE 
summaries but will be included and identified in the patient listings. 
11.2.2 
Other significant adverse events (OAE) 
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and DAEs.  Based on the expert’s judgement, 
significant adverse events of particular clinical importance may, after consultation with the 
Global Patient Safety Physician, be considered OAEs and reported as such in the Clinical 
Study Report.  A similar review of laboratory/vital signs/ECG data will be performed for 
identification of OAEs. 
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction 
or significant additional treatment. 


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11.2.3 
Vital signs, laboratory data, ECGs, ECHO/MUGA, physical examination and 
ophthalmologic examination 
For change from baseline summaries for vital signs, laboratory data, ECGs, and physical 
examination, the baseline value will be the latest result obtained prior to the start of study 
treatment. 
QTcF (Fredericia) will be calculated programmatically by AstraZeneca using the reported 
ECG values (RR and QT). 
QTcF = QT / RR^ (1/3) where RR is in seconds 
The denominator used in laboratory summaries will only include evaluable patients, in other 
words those who had sufficient data to have the possibility of an abnormality. For example: 

If a CTCAE criterion involves a change from baseline, evaluable patients 
would have both a pre-dose and at least 1 post-dose value recorded 

If a CTCAE criterion does not consider changes from baseline, to be 
evaluable the patient need only have 1 post dose-value recorded 
The denominator in vital signs data should include only those patients with recorded data. 
11.3 
Calculation or derivation of PK variables 
The final PK analyses will be the responsibility of Clinical Pharmacology and 
Pharmacometrics, AstraZeneca. 
Using appropriate PK software the available PK data will be used to derive PK parameters 
such as, but not restricted to, Cmax, AUC for Selumetinib, N-desmethyl selumetinib and any 
other metabolites determined. 
The selumetinib, N-desmethyl selumetinib and metabolite concentration-time profiles, along 
with the derived PK variables, will be listed for each patient per dose and dosing day and 
summarised appropriately, as described in the SAP. 
Population PK models may be used to derive the PK parameters and will aim to characterise 
variability in the population by investigating the influence of covariates such as weight, age, 
sex, and/or concomitant medications.  In addition, if the data are suitable, potential 
relationships between plasma selumetinib and N-desmethyl selumetinib concentrations will be 
investigated using a graphical approach and/or appropriate PK/PD modelling techniques.  A 
detailed PK analysis plan will be produced prior to any such investigations and will be 
reported separately. 
11.4 
Calculation or derivation of pharmacogenetic variables 
Genetic data (except BRAF and NRAS data) will be reported separately to the CSR for this 
study. 


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11.5 
Calculation or derivation of biomarker variables  
11.5.1 
Analysis of NRAS and BRAF 
Tumour samples will be collected as outlined in the study plan and assessed for BRAF and 
NRAS biomarkers to identify patients for this primary patient population. 
11.5.2 
Further biomarker research analysis 
Methods of analysis for all other biomarker research may include investigation of genetic 
variability, gene expression profiling, protein expression profiling. 
12. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
12.1 
Description of analysis sets 
12.1.1 
Intention to treat (ITT) analysis set 
The ITT analysis set will include all randomised patients. The ITT analysis set will be used for 
all efficacy analyses and treatment groups will be compared on the basis of randomised 
treatment, regardless of the treatment actually received. Patients who were randomised but did 
not subsequently go on to receive study treatment will be included in the ITT analysis set. 
12.1.2 
BRAF/NRAS mutation positive analysis set 
For the analysis of the BRAF and NRAS mutation positive population (primary objective), 
only those patients from the ITT population with genetic samples that are positive for BRAF 
or NRAS will be included. 
12.1.3 
Treatment-compliant (TC) analysis set 
The treatment-compliant analysis set will be a subset of the ITT population containing patients 
that adhered to the minimum study treatment requirements specified in Section 3.1.1, i.e. 
patients who take study treatment twice daily for a minimum of 7 consecutive days prior to 
RAI therapy, on the day of RAI therapy, and for 5 consecutive days afterwards. Patients must 
also have had their RAI dose.  
The TC analysis set will be used as a sensitivity analysis for the primary endpoint. 
12.1.4 
Safety analysis set 
The safety analysis set will consist of all patients who received at least one dose of 
randomised treatment and for whom post dose data are available. Safety data will not be 
formally analysed but summarised using the safety analysis set, according to the treatment 
combination received, ie, erroneously treated patients (eg, those randomised to treatment A 
but actually given treatment B) will be summarised according to the treatment they actually 
received. 


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12.1.5 
PK analysis set 
PK data will be analysed according to treatment received.  This population will comprise all 
patients who receive study treatment as per protocol and do not violate or deviate from the 
protocol in ways that would significantly affect the PK analyses.  The population will be 
defined by the AstraZeneca Study Team Physician, Pharmacokineticist and Statistician prior 
to any analyses being performed. 
12.2 
Methods of statistical analyses 
A comprehensive SAP will be prepared prior to start of recruitment (first subject in).  
Since there are two correlated primary comparisons of interest (selumetinib vs. placebo in the 
overall population and selumetinib vs. placebo in the mutation-positive population), the 
Dunnett and Tamhane step-up procedure will be used to control the type I error rate (Dunnett 
and Tamhane 1992, Fernandes & Stone 2011). This procedure is an adaptation of the 
Hochberg approach, which accounts for the correlation between the primary endpoint 
comparisons. The correlation between the primary endpoint comparisons will be calculated as 
w, where w is the proportion of the overall population who are in the mutation positive sub-
group. The associated significance level for declaring statistical significance in the mutation 
positive sub-group adjusting for this correlation to maintain an overall 5% type I error rate 
whilst assigning 4% to the overall population will then be derived. For example, assuming that 
55% of the overall population are in the mutation-positive sub-group, the correlation is 0.74. 
Using Dunnett and Tamhane step-up procedure, significance would therefore be declared if 
both the overall and mutation positive populations are significant at the 5% two-sided level, or 
if either the overall population is significant at the 4% level or the mutation-positive 
population is significant at the 1.625% level. 
12.2.1 
Complete remission rate at 18 months post-RAI treatment 
The endpoint of complete remission rate will be compared between selumetinib in 
combination with RAI, and placebo in combination with RAI in the overall population using a 
logistic regression model with covariates histology status (papillary, follicular, poorly 
differentiated), mutation status (BRAF/NRAS positive, BRAF/NRAS negative) and age, 
provided there are enough data points for a meaningful analysis.  
The primary endpoint of complete remission rate will be compared between selumetinib in 
combination with RAI vs. placebo in combination with RAI in the mutation positive 
population using a logistic regression model with covariates histology status (papillary, 
follicular, poorly differentiated) and age, provided there are enough data points for a 
meaningful analysis. 
For each covariate, if the status is missing or unknown, patients will be assigned to the status 
that the majority of patients are known to have, e.g. if 55% of patients with known mutation 
status are BRAF/NRAS positive and 45% are BRAF/NRAS negative, a patient with missing 
mutation status will be assigned BRAF/NRAS positive. If a value for the continuous covariate 
age is missing, the mean will be imputed. 


Clinical Study Protocol 
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Date 3rd April 2013 
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The results of the analysis will be presented in terms of an odds ratio together with its 
associated 95% profile likelihood confidence interval and 2-sided p-value. The p-value will be 
based on twice the change in log-likelihood resulting from the addition of a treatment factor to 
a model that contains the covariates defined above. The complete remission rate will be 
estimated for each treatment arm. 
Sensitivity analyses 
The primary endpoint analysis will be repeated using the treatment-compliant population. 
A sensitivity analysis will be performed in which patients that were identified as being in 
complete remission outside of the specified time windows will be included in the logistic 
regression analysis and classed as being in complete remission to ensure there is no evaluation 
time bias between arms.  
Elevated TSH can be caused by poor compliance and can mean a patient is less likely to 
achieve remission. A sensitivity analysis will be performed in which patients with high TSH 
are excluded from the logistic regression. A high TSH is defined as a value >10 mIU/L 
recorded at any point by standardised central laboratory analysis. 
The extent to which the treatment effect is consistent across the subgroups histology status, 
mutation status, gender, race and age will be assessed for the overall primary population and 
across the subgroups histology status, gender, race and age for the mutation positive primary 
population. The presence of a quantitative interaction will be assessed by means of an overall 
global interaction test. This will be performed by comparing the fit (likelihood ratio test) of a 
model including all covariate-by-randomised treatment interaction terms, treatment and 
covariate terms with a model that excludes the interaction terms. If the global interaction test 
is found to be statistically significant  at the 10% significance level, an attempt to determine 
the cause and type of interaction will be made. Stepwise backward selection will be performed 
on the saturated model, whereby (using a 10% level throughout) the least significant 
interaction terms are removed one-by-one and any newly significant interactions re-included 
until a final model is reached where all included interactions are significant and all excluded 
interactions are non-significant.  Throughout this process all main effects will be included in 
the model regardless of whether the corresponding interaction term is still present.  This 
approach will identify the factors that independently alter the treatment effect and prevent 
identification of multiple correlated interactions. 
For quantitative interactions identified, the presence of any qualitative interactions will be 
assessed using the approach of Gail and Simon (Gail & Simon 1985). For categorical 
covariates the test statistics, based on the appropriate degrees-of-freedom, can be taken 
directly from the paper. For the continuous covariate, the approach will be adapted as follows:  
Identify the cut-point (-E1/E3) of the covariate where the odds ratio for the treatment effect is 
1, where E1 is the treatment parameter estimate and E3 is the treatment-by-covariate parameter 
estimate. Re-analyse the data separately for the values of the covariate above and below the 
cut-point and use the separate chi-square values in the Simon and Gail test. 


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Subgroup data (histology status, mutation status, gender, race and age) will be summarised by 
a forest plot where the odds ratio is plotted on the log scale. For this, age will be categorised 
as d45 or >45 years. The treatment effect and confidence intervals for each level of the 
subgroup will be obtained from a single model that contains a treatment, factor and treatment-
by-factor interaction term.  
12.2.2 
Clinical remission rate at 18 months post-RAI treatment 
The secondary endpoint of clinical remission rate will be analysed (for both study 
populations) as described in Section 12.2.1. 
12.2.3 
Thyroid cancer recurrence 
Very few thyroid cancer recurrences are expected on this study, therefore no formal analysis 
of thyroid cancer recurrence data will be performed; data will be listed and summarised.  
12.2.4 
Survival status 
Very few deaths are expected on this study therefore no formal analysis of survival data will 
be performed; data will be listed and summarised. Kaplan-Meier plots of survival may 
produced if appropriate.  
12.2.5 
Further therapy 
No formal analysis of further therapy data will be performed; data will be listed and 
summarised. Kaplan-Meier plots of time to further therapy may produced if appropriate. 
12.2.6 
Safety data analysis 
Safety data will not be formally analysed. All patients who commenced study treatment will 
be included in the assessment of safety and will be summarised by treatment received. 
12.2.7 
PK data analysis 
The selumetinib, N-desmethyl selumetinib and metabolite concentration-time profiles, along 
with the derived PK variables, will be listed for each patient per dose and dosing day and 
summarised appropriately. 
12.2.8 
Genetics 
Any genetic data analysis (other than BRAF and NRAS) will be reported outside the CSR for 
this study. 
12.2.9 
Biomarker data 
BRAF and NRAS mutation assessment of tumour biopsy will be used to identify patients for 
this primary patient population.  
The results of any other exploratory biomarker investigations will be reported outside of the 
CSR. 


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12.2.10 
Interim analyses 
There are no interim analyses planned for this study.  
12.3 
Determination of sample size 
The sample size for this study was selected to be consistent with the research hypothesis as 
described in Section 1.2. 
The two primary objectives of the study are to compare the efficacy of selumetinib with RAI 
versus placebo with RAI, by assessment of the complete remission rate at 18 months post-RAI 
treatment in the overall study population, and in a sub-group of patients whose tumours have 
BRAF and NRAS mutations. Assuming the true complete remission rates in the overall study 
population are 30% and 50% for the placebo and selumentinib-containing arms, respectively, 
a total of 228 patients, randomised in a 2:1 ratio (152 and 76 patients in the selumentinib and 
placebo-containing arms, respectively) provides 80% power to show statistical significance, 
based on a two-sided 4% significance level. Assuming that the prevalence of the mutation-
positive sub-group described is 55%, and the true complete remission rates in the mutation-
positive sub-group are 30% and 62% for the placebo and selumentinib-containing arms, 
respectively, the expected numbers of 84 mutation-positive patients in the selumentinib arm 
and 42 mutation-positive patients in the placebo arm at the time of the analysis, provides 80% 
power to show statistical significance, based on a two-sided 1% significance level. 
12.4 
Data monitoring committee  
Due to the short treatment duration in this study there will not be a data monitoring committee 
for this study. 


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13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED 
BY THE INVESTIGATOR 
13.1 
Medical emergencies and AstraZeneca contacts 
The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study. A medical emergency usually 
constitutes an SAE and is to be reported as such, see Section 6.5.4 
In the case of a medical emergency the investigator may contact the Study Delivery Team 
Physician. If the Study Delivery Team physician is not available, contact the Study Delivery 
Team Leader. 
Name  
Role in the study  
Address & telephone number 
 
AstraZeneca Physician 
responsible for the protocol at 
central R&D site 
 
 
 
 
 
 
 
 
 
AstraZeneca Study Delivery 
Team Leader responsible for 
the protocol at central R&D 
site 
 
 
 
 
 
 
 
 
24-hour emergency cover at central 
R&D site. 
24-hour emergency cover at 
central R&D site.  
 
 
 
 
 
13.2 
Overdose  
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the relevant 
AE modules in the CRF and on the Overdose CRF module. 
An overdose without associated symptoms is only reported on the Overdose CRF module. 
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If an overdose on an AstraZeneca study drug occurs in the course of the study, then 
investigators or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site. 
For overdoses associated with SAE, standard reporting timelines apply, see Section 6.5.4.  For 
other overdoses, reporting should be done within 30 days. 
13.3 
Pregnancy 
All outcomes of pregnancy should be reported to AstraZeneca. 
13.3.1 
Maternal exposure 
If a subject becomes pregnant during the course of the study, investigational product should be 
discontinued immediately. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication.  Congenital abnormalities/birth defects and spontaneous 
miscarriages should be reported and handled as SAEs.  Elective abortions without 
complications should not be handled as AEs.  The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should be followed up and documented even if the subject was discontinued from the study. 
If any pregnancy occurs in the course of the study, then investigators or other site personnel 
inform appropriate AstraZeneca representatives immediately, or no later than 24 hours of 
when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
days for SAEs, see Section 6.5.4 and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is used 
to report the outcome of the pregnancy. 
13.3.2 
Paternal exposure 
The outcomes of any conception occurring from the date of the first dose, until 30 days after 
last dose, must be followed up and documented in the “Pregnancy Outcome Report” form. 
Male patients must refrain from fathering a child for 12 weeks following the last dose of study 
treatment, since the potential for chromosomal aberrations in male gametes, and possible 
teratogenic effects thereof, has not yet been thoroughly investigated. Restrictions from 


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Study Code D1532C00065 
Edition Number 2 
Date 3rd April 2013 
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fathering children should also take into account local recommendations following therapy 
with RAI. 
Pregnancy of the patients’ partner is not considered to be an AE.  However, the outcome of all 
pregnancies (including spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented. 
14. 
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Edition Number 2 
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Revised Clinical Study Protocol 
 
Drug Substance 
Selumetinib (AZD6244) 
 
Study Code 
D1532C00065 
 
Edition Number 
3 
 
Date 
15 July 2013 
 
 
 
 
 
 
 
A Randomised, Double Blind Study to Compare the Complete Remission 
Rate Following a 5-Week Course of Selumetinib or Placebo and Single Dose 
Adjuvant Radioactive Iodine Therapy in Patients with Differentiated 
Thyroid Cancer  
 
 
Sponsor:  AstraZeneca AB, 151 85 Södertälje, Sweden 
AstraZeneca Research and Development 
site representative 
 
 
The following Amendment(s) and Administrative Changes have been made to this protocol since the date 
of preparation: 
Amendment No. 
 Date of Amendment 
 
Local Amendment 
No: 
 
Date of Local 
Amendment 
2 
 15 July 2013 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
Administrative 
Change No. 
 Date of Administrative 
Change 
 
Local Administrative 
Change No. 
 
Date of Local 
Administrative Change 
 
  
 
 
 
 
 
  
 
 
 
 
 
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
ONC.000−591−887.3.0 (Version Created 18 Jul 2013 15:47:33)
33'
33'


 
2(118) 
PROTOCOL SYNOPSIS 
 
A Randomised, Double Blind Study to Compare the Complete Remission 
Rate Following a 5-Week Course of Selumetinib or Placebo and Single Dose 
Adjuvant Radioactive Iodine Therapy in Patients with Differentiated 
Thyroid Cancer 
 
 
International Co-ordinating Investigator  
 
Study centre(s) and number of patients planned 
Approximately 228 patients with newly diagnosed differentiated thyroid cancer at high risk of 
primary treatment failure will be recruited from approximately 50 sites in Europe, South 
and/or North America.     
Objectives 
Primary objective 
To compare the efficacy of selumetinib with radioactive iodine therapy (RAI), versus placebo 
with RAI, by assessment of complete remission rate at 18 months post RAI treatment in the 
intention to treat (ITT) study population. Complete remission is defined in Section 6.4.1. 
Secondary objectives 
To compare the efficacy of selumetinib with RAI, versus placebo with RAI, by assessment of 
complete remission rate at 18 months post RAI treatment in a sub-group of patients with 
tumours known to be mutation positive for BRAF or NRAS (defined in Section 6.10.1). 
Complete remission is defined in Section 6.4.1. 
To compare the efficacy of selumetinib with RAI, versus placebo with RAI by assessment of 
clinical remission rate at 18 months post RAI treatment in the ITT study population. Clinical 
remission is defined in Section 6.4.6. 
To compare the efficacy of selumetinib with RAI, versus placebo with RAI by assessment of 
clinical remission rate at 18 months post RAI treatment in a sub-group of patients with 
tumours known to be mutation positive for BRAF or NRAS (defined in Section 6.10.1). 
Clinical remission is defined in Section 6.4.6. 
To assess the safety and tolerability of selumetinib with RAI compared to placebo with RAI. 
33'


Clinical Study Protocol Synopsis 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
3(118) 
To investigate the pharmacokinetics (PK) of selumetinib and N-desmethyl selumetinib when 
administered to patients with differentiated thyroid cancer. 
Exploratory objectives 
To explore subsequent thyroid cancer therapy given to patients who receive selumetinib with 
RAI, or placebo with RAI. 
To investigate the relationship between selumetinib and/or N-desmethyl selumetinib plasma 
concentrations/exposure and clinical outcomes, efficacy, AEs and/or safety parameters. 
To collect tumour, plasma and serum samples for potential future research on biomarkers 
relevant to DTC and response and resistance to study treatments. 
To collect and store DNA for future exploratory research into genes/genetic variation that may 
influence response (ie, distribution, safety, tolerability and efficacy) to selumetinib or RAI 
and/or susceptibility to cancer. 
Study design 
This is a double-blind, randomised, placebo-controlled study comparing the efficacy of a short 
course (approximately 5 weeks) of selumetinib (75 mg, orally twice daily) with adjuvant RAI, 
to placebo with RAI.  
Following recovery from surgery (1 or 2-stage total thyroidectomy), and screening to 
determine study eligibility, patients will be randomised and will take their assigned study 
treatment (selumetinib or placebo) twice daily for a period of approximately 5 weeks.  Study 
treatment will begin approximately 4 weeks prior to the planned day of single dose RAI 
therapy, and will be continuous until 5 days following RAI therapy.  Patients will be required 
to adhere to a standardised low iodine diet prior to their RAI therapy.  For each of the 2 days 
immediately prior to their planned RAI therapy, patients will receive a 0.9 mg intramuscular 
(IM) recombinant human TSH injection (rhTSH, Thyrogen), in order to stimulate iodide 
uptake (patients or clinicians choosing to prepare for RAI ablation by withdrawal of thyroid 
hormone treatment will be ineligible for this study).  Following the 2 consecutive days of 
rhTSH injections, patients will receive their planned RAI therapy as a fixed single 100 mCi 
(3.7 GBq) dose of 131I the immediate next day. Study treatment will be taken as normal on the 
day of RAI therapy, and will be discontinued 5 days following the patient’s RAI therapy. 
Following RAI therapy, each patient will be followed up for a period of 18 months until the 
primary endpoint assessment of complete remission. The biochemical analysis contributing to 
the 18 month primary endpoint of complete remission will be performed by standardised 
central methodology, and the radiological imaging for structural disease at the primary 
endpoint will be subject to a blinded independent central review. Additional thyroid cancer 
therapy (eg, surgery or RAI treatment) must only be given during the 18 month primary 
endpoint follow up period according to the pre-specified study re-treatment criteria (refer to 
Section 5.9). Patients who do receive re-treatment in the 18 months following their initial RAI 


Clinical Study Protocol Synopsis 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
4(118) 
therapy, will not have any 18 month primary endpoint assessments performed; they will 
remain in the study and enter standard of care follow up according to local practice. 
Following the primary endpoint assessments (or re-treatment), all randomised patients will be 
further followed-up at 3 years after their initial RAI treatment, in order to further assess both 
the clinical status of patients, and the safety profile of selumetinib and RAI beyond the 
primary analysis (refer to Section 6.4.8). 
Target patient population 
Patients with histologically or cytologically confirmed follicular cell derived differentiated 
thyroid cancer (including papillary thyroid cancer and all variants, follicular thyroid cancer 
and all variants, and poorly differentiated thyroid cancer), who are determined to be at high 
risk of primary treatment failure, as defined by any one of the following staging categories 
post-surgery: 

Primary tumour greater than 4 cm  

Primary tumour of any size with gross extrathyroidal extension outside the thyroid 
gland (T4 disease) 

N1a or N1b disease with at least 1 lymph node  1 cm 

N1a or N1b disease involving 5 or more lymph nodes (of any size)  
Patients with known distant metastatic disease will be excluded from this study. 
Investigational product, dosage and mode of administration 
Selumetinib Hyd-Sulfate (75 mg) will be administered orally twice daily as capsules (blue).  
The Hyd Sulfate formulation will be used in this study, and unless otherwise specified is the 
formulation referenced throughout this document.  
Comparator, dosage and mode of administration 
Placebo (to match selumetinib) will be administered orally twice daily. 
Duration of treatment 
The duration of study treatment (selumetinib/placebo) will be approximately 5 weeks in total 
(Day 36 will typically be the last day of study treatment, but this may be extended to a 
maximum of 43 days to allow the planned RAI to be postponed by up to 1 week if absolutely 
necessary). 


Clinical Study Protocol Synopsis 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
5(118) 
Outcome variable(s):  
Efficacy 
The primary outcome variable for this study is the rate of complete remission at 18 months 
post-RAI treatment.  Patients will be defined to be in complete remission if all of the 
following criteria can be demonstrated: 
1. 
Serum thyroglobulin (Tg) levels < 1ng/mL during rhTSH stimulation, in the 
absence of interfering Tg antibodies, as assessed by standardised central laboratory 
analysis. 
2. 
No confirmed evidence of thyroid cancera by neck US, as assessed by investigator 
site review. 
3. 
No confirmed radiological evidence of thyroid cancera, as assessed by blinded 
independent central review.  
4. 
No histopathological evidence of thyroid cancer on FNA/biopsy when performed, 
as assessed by investigator site review. 
5. 
No further thyroid cancer therapy was administered in the first 18 months following 
the initial RAI treatment. 
aConfirmation of evidence of structural DTC will be either histopathological (from a 
biopsy/FNA; as criterion 4 above), or RAI-avid disease (refer to Section 6.4.4.2). In this 
disease setting, structural abnormalities that are not RAI-avid and do not have confirmed 
histopathology consistent with DTC (ie are not biopsy proven) are considered benign in the 
absence of biochemical DTC. 
A secondary outcome variable will be the rate of clinical remission at 18 months post-RAI 
treatment, where clinical remission is defined on the basis of Tg, US and WBS assessments 
alone, without the additional radiological data.  
Safety 
AEs/SAEs, physical examination results, lab values, ECG, vital signs. 
All randomised patients will be followed for safety monitoring for 3 years following their RAI 
adjuvant treatment, in order to monitor for selumetinib and RAI-associated side effects. 
PK 
Where sample collection and PK analysis allow, derived PK parameters for selumetinib and  
N-desmethyl selumetinib will be produced which may include, but not be restricted to, Cmax 
and AUC.  Exploratory variables will be analysed outside the clinical study report (CSR). 


Clinical Study Protocol Synopsis 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
6(118) 
Statistical methods 
Approximately 228 patients will be randomised in a 2:1 ratio in this study. The primary 
analysis will be performed when patients have been followed for 18 months following their 
RAI treatment. The primary analysis population will comprise all randomised patients (ITT 
population) and the primary endpoint of complete remission rate at 18 months will be 
analyzed using a logistic regression model including treatment as the only covariate. Results 
will be presented in terms of the odds ratio, 95% confidence interval and associated p-value. 
Logistic regression modelling including treatment and covariates histology status, mutation 
status and age, will be performed as sensitivity analyses provided there are enough data points 
for a meaningful analysis.  
Assuming the true complete remission rates in the ITT study population are 30% and 50% for 
the placebo and selumetinib-containing arms, respectively, the study will have at least 80% 
power to demonstrate a statistically significant difference at the 5% (2-sided) significance 
level.  
All secondary endpoints will be analysed at the time of the primary analysis. Exploratory 
biomarker analysis may be analysed after the time of the primary analysis and reported 
separately to the CSR (apart from the somatic genetic data required for analysis of the second 
primary endpoint). 
All randomised patients will continue to be followed until the final study visit (3 years after 
their RAI treatment). At this time, data on clinical status, incidence of re-treatment and long-
term safety will be summarised. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
7(118) 
TABLE OF CONTENTS 
PAGE
 
TITLE PAGE...........................................................................................................1 
PROTOCOL SYNOPSIS.........................................................................................2 
TABLE OF CONTENTS.........................................................................................7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................14 
1. 
INTRODUCTION .................................................................................................19 
1.1 
Background............................................................................................................19 
1.1.1 
Thyroid Cancer ......................................................................................................19 
1.1.2 
Radioactive iodine treatment .................................................................................19 
1.1.3 
Risk stratified remission rates following RAI treatment .......................................20 
1.1.4 
The benefits of achieving remission ......................................................................22 
1.1.5 
Selumetinib ............................................................................................................23 
1.1.5.1 
MEK and NIS expression ......................................................................................23 
1.1.5.2 
Clinical data in thyroid cancer ...............................................................................25 
1.1.5.3 
Safety profile of selumetinib..................................................................................26 
1.2 
Research hypothesis...............................................................................................30 
1.3 
Rationale for conducting this study .......................................................................30 
1.4 
Benefit/risk and ethical assessment........................................................................31 
2. 
STUDY OBJECTIVES..........................................................................................31 
2.1 
Primary objective...................................................................................................31 
2.2 
Secondary objectives .............................................................................................31 
2.3 
Exploratory objectives ...........................................................................................32 
3. 
STUDY PLAN AND PROCEDURES ..................................................................32 
3.1 
Overall study design and flow chart ......................................................................32 
3.1.1 
Treatment Plan.......................................................................................................33 
3.1.2 
Follow-up plan.......................................................................................................34 
3.2 
Rationale for study design, doses and control group .............................................44 
4. 
PATIENT SELECTION CRITERIA.....................................................................46 
4.1 
Inclusion criteria ....................................................................................................46 
4.1.1 
Genetics research study (optional blood sample) ..................................................49 
4.1.2 
Biomarkers research study on tumour progression biopsy....................................49 
4.2 
Exclusion criteria ...................................................................................................49 
4.2.1 
Genetics research study (optional blood sample) ..................................................51 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
8(118) 
5. 
STUDY CONDUCT..............................................................................................52 
5.1 
Restrictions during the study .................................................................................52 
5.1.1 
Low-iodine diet......................................................................................................52 
5.1.2 
Other study restrictions..........................................................................................52 
5.2 
Patient enrolment, randomisation and initiation of investigational product..........53 
5.2.1 
Procedures for randomisation ................................................................................54 
5.3 
Procedures for handling patients incorrectly enrolled, randomised or 
initiated on investigational product........................................................................54 
5.4 
Blinding and procedures for unblinding the study.................................................54 
5.4.1 
Methods for ensuring blinding...............................................................................54 
5.4.2 
Methods for unblinding the study..........................................................................55 
5.5 
Treatments..............................................................................................................55 
5.5.1 
Identity of investigational product(s).....................................................................55 
5.5.2 
Doses and treatment regimens ...............................................................................55 
5.5.3 
Management of study treatment related toxicity ...................................................56 
5.5.3.1 
Selumetinib dose interruption or reduction............................................................56 
5.5.3.2 
Management and investigation of specific selumetinib related AEs.....................57 
5.5.4 
Additional study drugs...........................................................................................58 
5.5.4.1 
Thyrogen (rhTSH, thyrotropin alfa for injection)..................................................58 
5.5.4.2 
Radioactive iodine (RAI).......................................................................................58 
5.5.4.3 
Thyroid hormone supplementation (TSH suppression).........................................58 
5.5.5 
Study drug labelling...............................................................................................59 
5.5.6 
Storage ...................................................................................................................59 
5.6 
Concomitant medications.......................................................................................59 
5.7 
Treatment compliance............................................................................................60 
5.7.1 
Accountability........................................................................................................60 
5.8 
Discontinuation of investigational product............................................................60 
5.8.1 
Procedures for premature discontinuation of a patient from investigational 
product ...................................................................................................................61 
5.9 
Criteria for further thyroid cancer therapy during the study..................................61 
5.9.1 
Re-treatment prior to the 18 month primary endpoint assessments.......................61 
5.9.1.1 
Biochemical disease re-treatment criteria..............................................................62 
5.9.1.2 
Structural disease re-treatment criteria ..................................................................63 
5.9.1.3 
Patient management on study (up to the primary analysis at 18 months 
post-RAI) ...............................................................................................................63 
5.9.2 
Re-treatment after the 18 month primary endpoint assessments ...........................64 
5.10 
Withdrawal from study ..........................................................................................64 
5.11 
Replacement of patients.........................................................................................64 
6. 
COLLECTION OF STUDY VARIABLES...........................................................64 
6.1 
Recording of data...................................................................................................64 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
9(118) 
6.2 
Data collection at enrolment ..................................................................................64 
6.2.1 
Performance status definitions...............................................................................66 
6.3 
Post-operative imaging assessments for eligibility................................................66 
6.4 
Efficacy..................................................................................................................66 
6.4.1 
Complete remission ...............................................................................................66 
6.4.2 
Staged approach to primary endpoint assessments................................................67 
6.4.2.1 
Primary endpoint assessments Stage 1 ..................................................................70 
6.4.2.2 
Primary endpoint assessments Stage 2 ..................................................................71 
6.4.2.3 
Primary endpoint assessments Stage 3 ..................................................................74 
6.4.3 
Blood sample assessments for efficacy..................................................................74 
6.4.3.1 
Suppressed Tg........................................................................................................74 
6.4.3.2 
Stimulated Tg.........................................................................................................75 
6.4.3.3 
TSH........................................................................................................................75 
6.4.3.4 
Tg antibody (TgAb) ...............................................................................................76 
6.4.4 
Imaging assessments for efficacy ..........................................................................77 
6.4.4.1 
Neck ultrasound (US) ............................................................................................77 
6.4.4.2 
Whole body diagnostic 131I nuclear medicine scan (WBS) ...................................78 
6.4.4.3 
Neck MRI...............................................................................................................79 
6.4.4.4 
Chest CT ................................................................................................................80 
6.4.4.5 
Biopsy or fine needle aspirate (FNA) ....................................................................80 
6.4.4.6 
Information to be sent to the central imaging CRO...............................................81 
6.4.5 
Derivation of primary endpoint of complete remission.........................................82 
6.4.6 
Clinical remission ..................................................................................................84 
6.4.7 
Derivation of clinical remission status...................................................................84 
6.4.8 
Final study follow up at 3 years.............................................................................85 
6.5 
Safety .....................................................................................................................85 
6.5.1 
Definition of adverse events ..................................................................................85 
6.5.2 
Definitions of serious adverse event......................................................................86 
6.5.3 
Recording of adverse events ..................................................................................86 
6.5.3.1 
Disease progression ...............................................................................................89 
6.5.4 
Reporting of serious adverse events.......................................................................89 
6.5.5 
Laboratory safety assessment ................................................................................90 
6.5.6 
Physical examination .............................................................................................91 
6.5.7 
Cardiac monitoring ................................................................................................91 
6.5.7.1 
ECHO or MUGA ...................................................................................................91 
6.5.7.2 
Resting 12-lead ECG .............................................................................................91 
6.5.8 
Vital signs ..............................................................................................................92 
6.5.9 
Other safety assessments........................................................................................92 
6.5.9.1 
Pregnancy test ........................................................................................................92 
6.5.9.2 
Ophthalmologic examination.................................................................................92 
6.6 
Patient reported outcomes (PRO) – not applicable................................................92 
6.7 
Pharmacokinetics ...................................................................................................93 
6.7.1 
PK samples required ..............................................................................................93 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
10(118) 
6.7.2 
Determination of drug concentration.....................................................................93 
6.8 
Pharmacodynamics – not applicable......................................................................93 
6.9 
Pharmacogenetics ..................................................................................................94 
6.9.1 
Genetic blood sample at study entry......................................................................94 
6.10 
Biomarker analysis.................................................................................................94 
6.10.1 
BRAF and NRAS patient population ......................................................................94 
6.10.1.1 Archival tumour sample.........................................................................................94 
6.10.2 
Collection of plasma and serum for exploratory biomarker research....................95 
6.10.3 
Collection of disease progression tumour sample..................................................96 
7. 
BIOLOGICAL SAMPLING PROCEDURES.......................................................97 
7.1 
Volume of blood ....................................................................................................97 
7.2 
Handling, storage and destruction of biological samples ......................................98 
7.2.1 
Pharmacokinetic samples.......................................................................................98 
7.2.2 
Pharmacogenetic samples ......................................................................................98 
7.3 
Labelling and shipment of biohazard samples.......................................................99 
7.4 
Chain of custody of biological samples.................................................................99 
7.5 
Withdrawal of informed consent for donated biological samples .........................99 
8. 
ETHICAL AND REGULATORY REQUIREMENTS.......................................100 
8.1 
Ethical conduct of the study.................................................................................100 
8.2 
Patient data protection..........................................................................................100 
8.3 
Ethics and regulatory review................................................................................100 
8.4 
Informed consent .................................................................................................101 
8.5 
Changes to the protocol and informed consent form...........................................102 
8.6 
Audits and inspections .........................................................................................102 
9. 
STUDY MANAGEMENT BY ASTRAZENECA..............................................102 
9.1 
Pre-study activities...............................................................................................102 
9.2 
Training of study site personnel...........................................................................103 
9.3 
Monitoring of the study .......................................................................................103 
9.3.1 
Source data...........................................................................................................103 
9.4 
Study agreements.................................................................................................104 
9.4.1 
Archiving of study documents.............................................................................104 
9.5 
Study timetable and end of study.........................................................................104 
10. 
DATA MANAGEMENT BY ASTRAZENECA OR DELEGATE....................104 
11. 
EVALUATION AND CALCULATION OF VARIABLES BY 
ASTRAZENECA OR DELEGATE ....................................................................105 


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11.1 
Calculation or derivation of efficacy variable(s) .................................................105 
11.1.1 
Complete remission rate at 18 months post-RAI treatment.................................105 
11.1.2 
Clinical remission rate at 18 months post-RAI treatment....................................105 
11.1.3 
Thyroid cancer recurrence ...................................................................................105 
11.1.4 
Survival status......................................................................................................106 
11.1.5 
Further therapy.....................................................................................................106 
11.2 
Calculation or derivation of safety variable(s).....................................................106 
11.2.1 
Adverse events.....................................................................................................106 
11.2.2 
Other significant adverse events (OAE) ..............................................................106 
11.2.3 
Vital signs, laboratory data, ECGs, ECHO/MUGA, physical examination 
and ophthalmologic examination.........................................................................107 
11.3 
Calculation or derivation of PK variables............................................................107 
11.4 
Calculation or derivation of pharmacogenetic variables......................................107 
11.5 
Calculation or derivation of biomarker variables ................................................108 
11.5.1 
Analysis of NRAS and BRAF ...............................................................................108 
11.5.2 
Further biomarker research analysis ....................................................................108 
12. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION..........108 
12.1 
Description of analysis sets..................................................................................108 
12.1.1 
Intention to treat (ITT) analysis set......................................................................108 
12.1.2 
BRAF/NRAS mutation positive analysis set.........................................................108 
12.1.3 
Treatment-compliant (TC) analysis set................................................................108 
12.1.4 
Safety analysis set................................................................................................108 
12.1.5 
PK analysis set .....................................................................................................109 
12.2 
Methods of statistical analyses.............................................................................109 
12.2.1 
Complete remission rate at 18 months post-RAI treatment.................................109 
12.2.2 
Clinical remission rate at 18 months post-RAI treatment....................................111 
12.2.3 
Thyroid cancer recurrence ...................................................................................111 
12.2.4 
Survival status......................................................................................................111 
12.2.5 
Further therapy.....................................................................................................111 
12.2.6 
Safety data analysis..............................................................................................111 
12.2.7 
PK data analysis...................................................................................................111 
12.2.8 
Genetics................................................................................................................111 
12.2.9 
Biomarker data.....................................................................................................112 
12.2.10 
Interim analyses ...................................................................................................112 
12.3 
Determination of sample size...............................................................................112 
12.4 
Data monitoring committee .................................................................................112 
13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR ................................................................................................113 
13.1 
Medical emergencies and AstraZeneca contacts .................................................113 
13.2 
Overdose ..............................................................................................................113 


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13.3 
Pregnancy.............................................................................................................114 
13.3.1 
Maternal exposure................................................................................................114 
13.3.2 
Paternal exposure.................................................................................................114 
14. 
LIST OF REFERENCES.....................................................................................115 
 
LIST OF TABLES 
Table 1 
Remission rates in 2 independent data sets of risk-categorised 
patients with differentiated thyroid cancer - based on tumour size 
and lymph node status ..............................................................................21 
Table 2 
Example study treatment plan ..................................................................34 
Table 3 
Study Plan.................................................................................................37 
Table 4 
Study Plan for the 18 month Primary Endpoint Assessments..................42 
Table 5 
Criteria for biochemical decision making (based on standardised 
central analysis results).............................................................................73 
Table 6 
Programmatic derivation of complete remission status............................83 
Table 7 
Laboratory safety assessments .................................................................90 
Table 8 
Biomarker summary table ........................................................................97 
Table 9 
Volume of blood to be drawn from each patient......................................97 
 
LIST OF FIGURES 
Figure 1 
Study flow chart .......................................................................................36 
Figure 2 
Time course to achieving a suppressed Tg<1 ng/mL in patients 
receiving total thyroidectomy and RAI therapy .......................................45 
Figure 3 
Flow chart for staged primary endpoint assessments...............................69 
 
LIST OF APPENDICES 
 
Appendix A  
Signatures 
Appendix B  
Additional Safety Information 
Appendix C  
IATA 6.2 Guidance document 


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Appendix D  
Actions Required in Cases of Combined Increase of Aminotransferase and 
Total Bilirubin – Hy’s Law 
Appendix E  
Cockcroft-Gault Formula 
Appendix F 
Low Iodine Diet 
Appendix G  
Guidance for Management of Adverse Events in Studies of Selumetinib 


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Edition Number 3 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
124I 
Iodine-124 
131I 
Iodine-131 (radioactive iodine; RAI) 
AE 
Adverse event (see definition in Section 6.5.1) 
AJCC 
American Joint Committee on Cancer 
ALP 
Alkaline phosphatise 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
ATA 
American Thyroid Association 
ATC 
Anaplastic thyroid cancer 
AUC 
Area under the plasma concentration-time curve from zero to infinity 
BD 
Twice daily (dosing) 
bid 
bis in die – twice a day 
BNP 
B-type natriuretic peptide 
BP 
Blood pressure 
Bpm 
Beats per minute 
BRAF 
v-raf murine sarcoma viral oncogene homolog B1 
cm 
centimetres 
Cmax 
Maximum plasma concentration 
CRF 
Case report form (electronic/paper) 
CR 
Clinical remission 
CR 
Complete remission 
CSA 
Clinical study agreement 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse event 
DAE 
Discontinuation of investigational product due to adverse event 
DNA 
Deoxyribonucleic acid  
DTC 
Differentiated thyroid cancer 
D-TC-FCO 
Differentiated thyroid carcinoma of follicular cell origin 


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Abbreviation or 
special term 
Explanation 
DUS 
Disease under study 
EBRT 
External beam radiation therapy 
EC 
Ethics committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
ERK 
Extracellular signal-regulated kinases 
ETA 
European Thyroid Association 
FDG-PET 
2-[F-18]-fluoro-2-deoxy-D-glucose positron emission tomography 
FNA 
Fine needle aspiration 
FSH 
Follicle stimulating hormone 
FTC 
Follicular thyroid cancer 
G1 
Gap 1 phase of the cell cycle 
GCP 
Good clinical practice 
g/dL 
grams per decilitre 
GMP 
Good manufacturing practice 
hr 
hour 
I 
Iodine 
IATA 
International Air Transport Association 
IB 
Investigator brochure 
ICH 
International Conference on Harmonisation 
ICH M3 
The European Medicines Agency’s International Conference on Harmonisation 
Topic M3 – “Non-Clinical Safety Studies for the Conduct of Human Clinical Trials 
and Marketing Authorization for Pharmaceuticals” 
IM 
Intramuscular 
INR 
International normalised ratio 
International 
Co-ordinating investigator 
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or activities 
internationally.  
IP 
Investigational product  
ITT 
Intention-to-treat 
IUD 
Intrauterine device 
IV 
Intravascular 
IVRS 
Interactive voice response system 


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Abbreviation or 
special term 
Explanation 
IWRS 
Interactive web response system 
kg 
kilograms 
KRAS 
v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 
LH 
Luteinizing hormone 
LIMS 
Laboratory information management system 
LLOQ 
Lower limit of quantification 
LSLV 
Last patient last visit 
LT4 
Synthetic levothyroxine 
LV 
Left ventricular 
LVEF 
Left ventricular ejection fraction 
M0, M1, Mx  
Distant metastasis status (TNM cancer staging system) 
MAPK 
Mitogen-activated protein kinase 
mCi 
millicuries 
MedDRA 
Medical dictionary for regulatory activities 
MEK 
MAPK/ERK kinase 
MI 
Myocardial infarction 
g/L 
micrograms per litre 
m 
micrometers 
mIU/L 
milli-International units per litre 
mg 
milligrams 
mg/day 
milligrams per day 
mL 
millilitres 
mL/min 
millilitres per minute 
mm 
millimetres 
mm3 
cubic millimetres 
ms 
milliseconds 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
MSKCC 
Memorial Sloan Kettering Cancer Center 
MTD 
Maximum tolerated dose 
MUGA 
Multi-gated acquisition scan 
N0, N1, Nx etc 
Lymph node disease stage (TNM cancer staging system) 
N/A 
Not applicable 
ng/mL 
nanograms per milliliter 


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Abbreviation or 
special term 
Explanation 
NIS 
Sodium iodide symporter 
NOEL 
No observed effect level 
NSCLC 
Non-small cell lung cancer 
NTRK 
Neurotrophic tyrosine kinase, receptor, type 1 
NYHA 
New York Heart Association 
OAE 
Other significant adverse event (see definition in Section 6.5) 
PDTC 
Poorly differentiated thyroid carcinomas 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PGx 
Pharmacogenetic research 
PI 
Principal investigator  
PK 
Pharmacokinetics 
PRO 
Patient reported outcomes 
PTC 
Papillary thyroid cancer 
RAI 
Radioactive iodine (131I) 
RET 
Ret proto-oncogene 
Rb 
Retinoblastoma protein 
RECIST 
Response Evaluation Criteria In Solid Tumours 
rhTSH 
Recombinant human thyroid stimulating hormone 
SAE 
Serious adverse event (see definition in Section 6.5.2). 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis software 
SBE-CD 
Sulphobutylether -cyclodextrin 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
SUV 
Standard uptake value 
T0, T1, Tx etc 
Primary tumour disease stage (TNM cancer staging system) 
T4 
Free thyroxine 
Tg 
Thyroglobulin 
TgAb 
Thyroglobulin antibody 
TNM 
Tumour, nodes, metastasis cancer staging system 
TPGS 
D- tocopheryl polyethylene glycol 1000 succinate 


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Abbreviation or 
special term 
Explanation 
TPO 
Thyroid peroxidase 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
US 
Ultrasound 
WBDC 
Web based data capture 
WBS 
Whole body scintigraphy (also whole body scan) 
WHO 
World Health Organisation 
Wk 
Week 
 


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1. 
INTRODUCTION 
1.1 
Background 
1.1.1 
Thyroid Cancer 
There are approximately 56,500 new cases of thyroid cancer diagnosed in the USA per year, 
and approximately 34,000 new cases diagnosed in Europe per year.  Thyroid cancers are 
classified according to their histopathological characteristics into 4 main variants: papillary 
thyroid cancer (PTC, the most common), follicular thyroid cancer,  medullary thyroid cancer 
and anaplastic (undifferentiated) thyroid cancer.  The papillary and follicular types together 
can be classified as differentiated thyroid cancer (DTC), and make up approximately 95% of 
thyroid cancers. All DTC (including PTC) begins in the follicular cells of the thyroid gland 
and is termed “of follicular cell origin.”  Other, rarer variants of thyroid cancer of follicular 
cell origin include Hürthle cell carcinoma and poorly differentiated thyroid cancer (PDTC). 
DTC is generally indolent and has a natural history which is measured in decades if treated 
appropriately (up to 95% 10 year survival). However there are very limited options for 
patients who ultimately fail radioactive iodine therapy and develop distant refractory 
metastases, and most of these patients will succumb to their disease (Durante et al 2006).  
1.1.2 
Radioactive iodine treatment  
In addition to primary thyroid surgery, radioactive iodine (RAI, 131I) is the mainstay of 
therapy for patients with thyroid cancer of follicular origin. It is a targeted therapeutic 
approach that exploits the expression of the sodium iodide symporter (NIS) to deliver 
radiation selectively to thyroid cells, which is used as adjuvant therapy after thyroidectomy, 
and to treat recurrent and metastatic disease.   
Most patients with thyroid cancer of follicular origin have differentiated carcinomas which 
retain at least to some extent the biological properties of normal thyroid cells, including 
expression of NIS. Presence of this transporter is required for iodine uptake (Riesco-
Eizaguirre et al 2006). 
Following diagnosis, surgical resection of the thyroid gland with or without removal of the 
local lymph nodes is performed. Following surgical resection, a set of clinical-pathologic data 
(such as age at diagnosis, specific histological type, size of the primary tumour, extent of 
lymph node metastases, presence of distant metastases, gross extrathyroidal extension and 
completeness of resection) can be used to estimate the risk of recurrence and the risk of 
disease specific mortality. After surgery, radioactive iodine can be used for the following 
purposes: 
For diagnostic scanning to improve initial staging and extent of disease assessment. 
For ablation of the normal thyroid remnant (usually less than 2-3% of normal tissue remains 
after total thyroidectomy). This treatment facilitates follow-up by achieving an undetectable 
level of serum thyroglobulin and a subsequent negative diagnostic whole body RAI scan. 


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As adjuvant therapy, in an attempt to destroy microscopic residual disease in patients at 
intermediate to high risk of recurrence. 
As primary therapy in patients with unresectable RAI-avid loco-regional disease or distant 
metastases.   
Uptake of RAI by tumour tissue is a prerequisite for administration of RAI treatment and for 
its efficacy. Once patients develop distant metastatic disease, RAI uptake is observed in only 
two thirds of cases and less frequently in patients with aggressive disease (Durante et al 2006, 
Mazzaferri and Kloos 2001, Nemec et al 1979, Samaan et al 1985).  Patients with no uptake in 
metastatic foci are considered refractory to RAI, which is then no longer indicated. 
1.1.3 
Risk stratified remission rates following RAI treatment 
Several different risk stratification systems have been published for DTC.  The Union 
Internationale Contre le Cancer/American Joint Committee on Cancer (AJCC) staging system 
is the most commonly used, but it was developed to predict the risk of death rather than 
recurrence.  To overcome this limitation, the American Thyroid Association (ATA) published 
guidelines to grade the risk of recurrence into 3 categories (low, intermediate, and high) based 
on tumour-related parameters (pathological tumour-node-metastasis and histological variant) 
integrated with other clinical features, including the result of the first post-therapy RAI whole-
body scan and serum Tg measurement.  Although the ATA risk stratification system has been 
shown to better predict short-term clinically relevant endpoints of persistent and recurrent 
disease than the AJCC system, it does not adequately predict longer-term outcomes because 
the risk of persistent or recurrent disease changes following initial therapy. In addition, the 
ATA intermediate risk category includes a wide variety of potential risk factors that can have 
a significant influence on both short term and long-term outcomes (any tumour size, N1a/N1b 
node status, vascular invasion, extrathyroidal extension, aggressive histology).  
Recent evidence suggests that the likelihood of achieving remission varies depending on the 
size of the primary tumour, extent of invasion, or lymph node status as defined by number and 
size of affected nodes (refer to Table 1, Tuttle, unpublished sub-analysis of data from Tuttle et 
al 2010 and Vaisman et al 2012). 


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Table 1 
Remission rates in 2 independent data sets of risk-categorised patients 
with differentiated thyroid cancer - based on tumour size and lymph 
node status 
TNM 
status 
Description 
Remission ratea 
MSKCCb 
n=588 patients 
Remission ratea 
Brazilc 
n=506 patients 
T1 
Tumour diameter 2 cm or smaller 
40% 
59% 
T2 
Tumour diameter 2 - 4 cm 
47% 
52% 
T3 
Tumour diameter > 4 cm or with minimal extrathyroidal 
extension 
25% 
37% 
T4 
Tumour of any size extending to invade subcutaneous soft 
tissues, larynx, trachea, esophagus, recurrent laryngeal 
nerve, prevertebral fascia or encasing carotid artery or 
mediastinal vessels 
13% 
17% 
N0 
No metastatic nodes identified 
62% 
54% 
N1a 
Metastatic nodes in central neck (pretracheal, 
paratracheal, or prelaryngeal) 
31% 
30% 
N1b 
Metastatic nodes in lateral neck or superior mediastinum 
16% 
12% 
a Remission rate within a 2 year follow up period 
b unpublished sub-analysis of data from Tuttle et al 2010 
c unpublished sub-analysis of data from Vaisman et al 2012 
As can be seen patients with either T3 disease or N1a disease have remission rates that 
approximate 30%, while patients with T4 disease or N1b disease have remission rates that 
approximate 15%.  From a clinical perspective, these findings are not surprising since T3 
disease is very commonly associated with N1a disease, and T4 disease is often associated with 
N1b disease.  Therefore, the similarity in remission rates in T3 and N1a disease, and in T4 and 
N1b disease, is consistent with observations in clinical practice.   
It is important to note that in addition to the location of the lymph node metastases (N1a vs. 
N1b), the extent of lymph node metastases (size and number of involved nodes) is also a 
critical factor in assessing the risk of recurrence and risk of failing initial therapy (Randolph et 
al, 2012, Ricarte-Filho et al 2012). The complete remission rates from the MSKCC and 
Brazilian cohorts are based on patients with clinically significant, structurally evident N1a 
and/or N1b disease that required therapeutic neck dissections for clinically apparent metastatic 
disease (prophylactic neck dissections to remove sub-clinical disease were not performed in 
either the MSKCC or Brazilian cohorts).  For example, in a MSKCC series of 246 papillary 
thyroid cancer patients who presented with lymph node metastases at the time of diagnosis, a 
median of 6 metastatic lymph nodes were identified with a median maximal diameter of 1.3 
cm (Ricarte-Filho et al 2012).  Furthermore, multiple studies have demonstrated that small 
volume lymph node metastases which are usually identified as incidental findings in the 
fibroadipose tissue surrounding the thyroid, or as a result of prophylactic central neck 
dissections, are associated with a low risk of recurrence (Randolph et al, 2012, Ricarte-Filho 
et al 2012), and these may not even require RAI adjuvant therapy (and therefore would not be 


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appropriate subjects for the proposed study).  Therefore, to prevent patients with lower risk 
N1a or N1b small volume metastatic disease from enrolling into this study, a requirement is 
that subjects must have N1a or N1b disease involving 5 or more lymph nodes (of any size) or 
at least 1 lymph node  1 cm in the largest diameter. 
Since only approximately 30% of patients presenting with any of the following features are 
expected to achieve clinical remission following total thyroidectomy and RAI remnant 
ablation, they are at high risk of failing their primary treatment: 

Primary tumour greater than 4 cm 

Primary tumours of any size with gross extrathyroidal extension outside the thyroid 
gland (T4 disease) 

N1a or N1b disease with at least 1 lymph node  1 cm 

N1a or N1b disease involving 5 or more lymph nodes (of any size) 
Total thyroidectomy and RAI ablation is therefore very effective at inducing remission in low 
risk patients, however approximately 70% of patients with the above characteristics do not 
enter remission, and have an incomplete response to initial therapy with biochemical and/or 
structural evidence of persistent disease. 
1.1.4 
The benefits of achieving remission 
Thyroid cancer deaths are exceedingly rare if remission is achieved, and studies have shown 
that nearly all deaths ultimately occur in the group of patients who do not achieve remission. 
For example, two recent studies reported disease-specific deaths in 6% and 8% of the patients 
who did not achieve remission compared to 0% in patients who achieved remission with 
median follow-up times of 7 and 10 years respectively (Tuttle RM, unpublished sub-analysis 
of data from Tuttle et al 2010, Vaisman et al 2012).  This mortality rate continues to rise with 
longer periods of follow up with nearly all deaths from thyroid cancer being seen in the cohort 
of patients that failed to achieve remission.   
The importance of a successful initial therapy is demonstrated by the excellent prognosis that 
even high-risk patients have if therapy results in negative imaging and negative thyroglobulin 
levels after stimulation by TSH. The majority of patients who achieve remission do not 
relapse; recurrence rates are typically 1% to 4% over median follow-up periods of 5 to 10 
years for patients who achieve remission (Castagna et al 2011, Tuttle et al 2010, Vaisman et al 
2012).     
In patients that achieve remission, there are important clinical and psychological benefits. 
Patients that achieve remission are re-classified as low risk patients and require much less 
frequent follow-up. Thyroglobulin testing and imaging assessments are reduced in frequency, 
and less aggressive TSH suppressive therapy is required. This in turn reduces the longer-term 
risks of osteoporosis and atrial fibrillation that are known complications of supra-


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physiological dosing of levothyroxine, and reduces the anxiousness and fatigue that can result 
from the mildly hyperthyroid state caused by TSH suppression. 
If remission is not achieved with initial therapy, many patients will be subjected to additional 
therapies (eg, more RAI, surgery, external beam irradiation), in an effort to control disease 
progression and achieve a cure.  Therapeutic RAI is associated with a cumulative dose-related 
risk of early and late-onset complications such as salivary gland damage, dental caries, 
nasolacrimal duct obstruction, and decreased fertility (Cooper et al 2009). Furthermore, a 
dose-dependent relationship is also seen between cumulative administered RAI activity and 
the subsequent occurrence of secondary malignancies (Rubino et al 2003, Sawka et al 2009). 
All of these risks and symptoms constitute significant quality of life issues for the patient. The 
inconvenience of repeating a low iodine diet, the associated radiation safety precautions and 
missed days of work are additional factors the patient must consider.  Additional surgery 
carries associated risks related to anesthesia, nerve damage (resulting in hoarseness, 
permanent tracheotomy in rare occasions, drooping eye lid, loss of control of shoulder 
muscles and loss of sensation in the neck), increased scarring in the neck (resulting in 
discomfort and difficulty swallowing), and damage to the parathyroid glands (resulting in 
hypocalcemia and a lifetime need for vitamin D and calcium supplementation and frequent 
blood tests). Thus avoidance of further therapy is beneficial to the patient. 
Unfortunately, additional therapy is often less effective, particularly in patients with persistent 
structural disease (Vaisman et al, 2011). Further RAI can be given to patients that have 
persistent biochemical evidence of disease, and although repeat RAI is often less effective 
than the initial RAI treatment (especially for patients with persistent structural disease), it can 
be effective at driving some patients with persistent biochemical disease into remission. Thus, 
strategies designed to improve the tumouricidal effect of the initial RAI dose should result in 
higher remission and cure rates. 
An intervention that enhances the effectiveness of initial therapeutic RAI in higher risk 
patients (the target population for this study), should result in higher remission rates and 
remove the need for further therapy, and would thus be of clear benefit to patients. 
1.1.5 
Selumetinib 
Selumetinib is a potent, selective, noncompetitive inhibitor of MEK, licensed for development 
by AstraZeneca Pharmaceuticals from Array BioPharma.  Selumetinib was discovered by 
Array Biopharma and had the designation ARRY 142886.  Other laboratory code names used 
during the development of this molecule are AR00142886 and AR-142886-X (where X refers 
to a sequential lot number).  Array BioPharma was responsible for the first-into-human study; 
the remainder of the clinical development programme for oncology indications is the 
responsibility of AstraZeneca.  AZD6244 has now been assigned the international non-
proprietary name selumetinib.   
1.1.5.1 
MEK and NIS expression  
Papillary thyroid cancer (PTC), which is the most common form of the disease, is 
characterised by a set of genetic alterations, all of which result in the activation of 


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RAF/MEK/ERK signalling. Of these genetic lesions the most common is the typical V600E 
mutant of BRAF also found in other cancers, most notably melanoma. The other genetic 
lesions occur in receptor tyrosine kinases (RET and NTRK1), and in RAS (N and HRAS). In 
total these mutations in effectors of ERK signalling account for approximately 70% of 
papillary thyroid cancer (Kimura et al 2003, Soares et al 2003). BRAF itself is seen in at least 
38% of PTC, and is also found in poorly differentiated and anaplastic thyroid carcinomas with 
a prevalence of 12% and 50%, respectively (Nikiforova et al 2003, Ricarte-Filho et al 2009). 
These genetic mutations are mutually exclusive and suggest the importance of 
RAF/MEK/ERK signalling in papillary thyroid cancer.  
With regard to the impact on efficacy of RAI therapy, one of the primary effects of activation 
of the RAF/MEK/ERK signalling pathway is a significant and sustained down regulation of 
the sodium iodide symporter (NIS) which is responsible for the uptake of iodine into thyroid 
cells and is required for the uptake of therapeutic 131I into thyroid cancer cells. Studies have 
demonstrated that the expression of NIS (and other genes typical of differentiated thyroid 
cells) is suppressed by activation of RAF/MEK/ERK signalling in mouse models of the 
disease (Franco A et al. 2011). In mice engineered to express V600E BRAF in thyroid cells, 
expression of NIS and other thyroid differentiation markers is reduced (Knauf et al 2005). 
These mice develop papillary thyroid cancers with dedifferentiated features. Further data 
using a mouse model of thyroid-specific inducible expression of V600E BRAF, show that 
V600E BRAF activation suppresses expression of NIS, thyroid peroxidase (TPO) and 
thyroglobulin (Tg), and blocks 124I uptake, all of which are re-established once expression of 
oncogenic BRAF is turned off. Treatment of mice expressing the induced V600E BRAF with a 
MEK inhibitor also re-established NIS expression and 124I uptake in the poorly differentiated 
thyroid carcinomas (PDTC) (Chakravarty D et al 2011). Constitutive activation of MAPK 
signalling also inhibits the expression of thyroid peroxidase and thyroglobulin in BRAF-
induced murine thyroid cancers. Genetic or pharmacological blockade of the pathway restores 
their expression, and consequently the ability to incorporate iodine into tyrosine (iodine 
organification), which is associated with greater retention time of 131I in cancer cells 
(Chakravarty D et al 2011). Other MAPK activating alterations common to thyroid cancer can 
also cause de-differentiation.  Over-expression of either the G12V HRAS mutant or RET/PTC 
in thyroid cancer cells suppresses NIS, thyroglobulin and thyroid peroxidase expression, 
which is restored with MEK inhibitor treatment (Knauf et al 2003, De Vita et al, 2005).  These 
experiments provide a pre-clinical proof of concept that inhibition of ERK signalling by MEK 
inhibitors can reverse the suppression of NIS, TG and TPO expression and re-establish iodine 
incorporation into PTC. 
NIS expression in clinical thyroid cancer samples 
Analysis of clinical tumour samples for NIS expression indicates a relative loss of NIS 
expression (and the expression of other thyroid specific genes) relative to normal thyroid 
tissue (Durante et al 2007; Espadinha et al 2009). Furthermore, NIS expression is lower in 
BRAF mutant tumours than in those without BRAF mutation (Durante et al 2007; Morai et al 
2011; Romei et al 2008).  In a well differentiated rat thyroid cell line model, expression of 
RET/PTC, mutant HRAS, or constitutively active MEK1, blocked TSH-induced expression of 
Tg and NIS; an effect that was reversed by MEK inhibition.  These data are consistent with 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
25(118) 
the hypothesis that activation of MEK, regardless of the upstream activating mutation is a key 
factor in the loss of thyroid differentiation specific gene expression including NIS (Knauf et al 
2003). 
In summary, this data predicts that both an unselected and genetically selected population may 
benefit from treatment with a MEK inhibitor and RAI. This study will thus assess two 
populations for the primary endpoint of complete remission rate at 18 months; the genetic ‘all 
comer’ population, and also a population of patients with tumours carrying BRAF or NRAS 
mutations, as these are known to constitutively activate the MEK signalling pathway. 
Treatment with a MEK inhibitor may thus be hypothesised to deliver a greater treatment effect 
in these patients. However, the pathway can be activated in many ways such that other 
patients may also benefit.  
1.1.5.2 
Clinical data in thyroid cancer 
The preclinical data generated to date suggests the clinical hypothesis that MAPK pathway 
inhibition in patients with RAI-refractory tumours will result in reacquisition of RAI uptake 
and renewed susceptibility to therapeutic 131I.  To test this hypothesis, an investigator-
sponsored selumetinib pilot study has been performed at MSKCC for patients with RAI-
refractory recurrent or metastatic differentiated thyroid carcinoma of follicular cell origin 
entitled, “Reacquisition Of RAI Uptake Of RAI-Refractory Metastatic Thyroid Cancers By 
Pre-treatment With The Selective MEK Inhibitor Selumetinib: A Pilot Study” (Ho et al 2012).  
In this study, the RAI avidity of thyroid tumours was quantified by lesional dosimetry with 
124I PET imaging in patients, before and after 4 weeks of treatment with selumetinib.  For 
patients whose tumours reacquired the ability to take up RAI, 131I treatment was administered, 
and tumour response was assessed both radiographically and with measurement of the serum 
tumour marker thyroglobulin (Tg).   
20 patients were treated with selumetinib in this pilot study.  Of the 20 patients, 9 patients had 
tumours with the V600E BRAF mutation, 5 patients had tumours with NRAS mutations at 
codon 61, 3 patients had tumours with RET/PTC rearrangements, and the remaining 3 patients 
were wild-type for these alterations. Twelve of the 20 patients in the study demonstrated 
increased tumoural 124I uptake, and 8 of these 12 patients achieved sufficient iodine reuptake 
to warrant treatment with 131I.  Interestingly, 5 of these patients were found to have NRAS 
mutations, one a BRAF mutation, one a RET/PTC rearrangement and one patient was wild-
type.  Further genotyping and cytogenetic analysis is ongoing to discover other potential 
oncogenic drivers that may have promoted susceptibility to this therapeutic strategy.  The 
increased iodine incorporation as quantified on the 124I scans translated to clinical efficacy 
with RAI therapy.  Reduction in tumour size by RECIST criteria was achieved in all RAI-
treated patients, with 5 confirmed partial responses and 3 patients with stable disease.  
Substantial decreases in serum thyroglobulin following RAI therapy were achieved in all 8 
RAI-treated patients.  The mean percent reduction in serum thyroglobulin achieved “post-
RAI” (2 months after RAI treatment) compared to “pre-RAI” (within 3 weeks before RAI 
treatment) was 89%.     


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
26(118) 
Data from the pilot study also suggests that pre-treatment with selumetinib selectively 
increased RAI uptake in tumoural lesions compared to non-thyroidal tissue (salivary gland). 
This pilot study demonstrates that MAPK pathway inhibition can modulate RAI uptake in the 
most difficult clinical scenario: patients with resistance to RAI therapy. Most patients in the 
pilot clinical study described above had many metastatic lesions, some of which were 
refractory to RAI at baseline, and some of which were partially RAI avid at baseline.  
Importantly, selumetinib not only restored RAI uptake in previously refractory lesions, but 
also increased RAI uptake in most partially-avid lesions (typically by more than 100% 
compared to the baseline value; 3 to 7 fold increases in maximum SUVs in such lesions were 
consistently observed). This provides a strong rationale to develop this strategy in the adjuvant 
setting for RAI naïve patients, with the goal of further enhancing what is more likely to be 
RAI-susceptible disease for patients at high risk of primary treatment failure.    
In addition to the pilot study described above, a phase II study of 100 mg bid selumetinib 
(previous mix-and-drink formulation) in 39 patients with RAI-refractory differentiated 
metastatic thyroid cancer has also been completed (Hayes et al 2012). This study involved 
continuous monotherapy dosing of selumetinib and no RAI treatment. The results 
demonstrated few clinical responses (one partial response in 32 evaluable patients), but 
demonstrated a 66% stable disease rate; median PFS in this poor-prognosis cohort was 
33 weeks in patients with mutations in BRAF V600E, and 32 weeks in all-comers. Although 
this study was conducted with the mix and drink formulation (from which selumetinib 
exposure may be lower), the efficacy of selumetinib as monotherapy in this population was 
disappointing. 
Taken together, these data suggest a strong rationale for investigating selumetinib with RAI in 
patients with DTC.  Given the known prevalence of MEK pathway activation in patients with 
DTC, and both the pre-clinical and clinical data seen when selumetinib is added to RAI, 
increasing iodine uptake, specifically with respect to selumetinib’s ability to upregulate NIS 
expression, adding selumetinib to standard of care RAI treatment has the potential to provide 
important clinical benefit.  This benefit may extend to all patients regardless of their genotype, 
or it may be greater in those patients with tumours driven by mutations in the MEK pathway. 
This study will allow these hypotheses to be tested. 
1.1.5.3 
Safety profile of selumetinib 
Array BioPharma was responsible for the first study of selumetinib into patients.  The 
remainder of the oncology clinical development programme is the responsibility of 
AstraZeneca.  Selumetinib is currently in phase II development, and has been used as both 
monotherapy and in combination with other anti-cancer agents, in a variety of adult solid 
tumour settings (eg, pancreatic cancer, colorectal cancer, melanoma and NSCLC), and 
paediatric cancer patients. 
The formulation taken into the phase I clinical programme by Array Biopharma was an 
extemporaneous preparation of an oral suspension of selumetinib as the free-base in an 
aqueous solution of sulphobutylether -cyclodextrin (SBE-CD, Captisol®), referred to as the 
free-base suspension formulation (mix and drink).  The AstraZeneca phase II monotherapy 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
27(118) 
clinical programme also utilised this formulation.  Subsequent formulation development 
resulted in a capsule formulation of selumetinib as the hydrogen sulphate salt (AZD6244 Hyd-
Sulfate), which will be used in this study. The maximum tolerated dose (MTD) for the 
suspension formulation was determined to be 100 mg twice daily, whereas for the capsule, the 
MTD was determined to be 75 mg twice daily. The emerging safety and tolerability profile of 
the capsule formulation is broadly consistent with that of the suspension formulation, although 
a higher frequency of fatigue and nausea has been reported with the capsule formulation 
compared to the suspension formulation in the phase II monotherapy studies. 
As of April 2012, over 1200 patients have received selumetinib as monotherapy or in 
combination with other anti-cancer agents in clinical studies (AstraZeneca and non 
AstraZeneca-sponsored studies, including investigator-sponsored studies). 
Two phase I studies (D1532C00005, D1532C00020) were performed with the Hyd-Sulfate 
formulation. Comparison of the frequencies from Study D1532C00005 and the AZ-sponsored 
phase II monotherapy studies described below, shows that there are higher percentages of 
patients reporting the most frequent AEs such as fatigue, dermatitis acneiform, diarrhoea, 
nausea and peripheral oedema with the Hyd-Sulfate formulation. This may be due to the 
higher plasma exposures achieved with the capsule formulation, but may also be in part as a 
consequence of the more heavily pre-treated patient population in study D1532C00005 having 
lower tolerances to developing toxicity. 

The frequencies of common AEs observed in Study D1532C00020 were generally 
more similar to that of Study D1532C00003 (free-base suspension formulation in a 
phase II population), which may mean that some of the differences in frequencies 
observed just reflect variations in the study population as the selumetinib safety 
profile is established. 
Two hundred and sixty nine (269) patients received selumetinib free base suspension 100 mg 
twice daily in 4 completed phase II monotherapy studies (D1532C00003, D1532C00008, 
D1532C00011, and D1532C00012). 

Rashes (including the preferred terms dermatitis acneiform, rash, rash 
maculopapular, rash macular, rash papular, acne, and folliculitis) were reported in 
approximately 70% of patients receiving treatment with selumetinib, and dermatitis 
acneiform was the most common AE term overall (54%).  Other commonly 
reported AEs were diarrhoea (49%), nausea (33%) and vomiting (24%).  Adverse 
events of peripheral oedema, periorbital oedema, and facial oedema were reported 
in 31%, 9%, and 4% of patients, respectively.  The AEs of fatigue or asthenia were 
reported in approximately 30% of patients in this phase II population.  Dyspnoea 
exertional or dyspnoea was reported in 13% of patients and, in individual studies, 
dyspnoea exertional was reported at a higher incidence in the selumetinib groups 
than in the comparator chemotherapy groups. 

Serious AEs were reported in 24% of patients receiving selumetinib monotherapy.  
The most frequently reported serious AEs were vomiting (1.5%), diarrhoea, 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
28(118) 
erysipelas, and pulmonary embolism (in 1.1% patients each).  Serious AEs of 
infections (bacterial sepsis, sepsis, infection, and bacterial arthritis) were reported in 
2.2% of patients. The most frequently related reported treatment-related SAE was 
vomiting (3 patients).  

In Study D1532C00003, small increases in blood pressure were observed after 1 
week on selumetinib, with mean increases of 7.4 mmHg (systolic, SBP) and 5.3 
mmHg (diastolic, DBP) at Week 8, compared with mean increases of 1.1 mmHg 
(SBP) and 0.5 mmHg (DBP) in the temozolomide comparator arm.  The AE of 
hypertension was reported in 18 patients (6.7%) receiving selumetinib in phase II 
monotherapy studies; 6 of these patients had hypertension at entry to the study, and 
a further 5 patients had documented risk factors for hypertension.  

Reversible asymptomatic reduction in left ventricular ejection fraction (LVEF) to 
below 55% has been reported in a small proportion of patients with advanced 
cancers in the monotherapy and randomised placebo controlled studies in 
combination with standard chemotherapies, with both formulations of selumetinib.  
In both placebo controlled studies no patient treated with selumetinib had severe 
LVEF impairment (< 35%) or symptomatic heart failure. Evidence of reversibility 
on continuing treatment with selumetinib has been demonstrated in some patients. 
LVEF scheduled assessments were only included in one phase II study 
(D1532C00003) and in the selumetinib group to evaluate a possible cardiac 
aetiology of the peripheral oedema reported in earlier studies. The median change in 
LVEF at Week 4 was 1.2 percentage points, and the individual change from 
baseline ranged from –20 to +19 percentage points. Adverse events of ejection 
fraction decreased, left ventricular dysfunction, or ventricular dysfunction were 
reported in a total of 5 patients (3.3%) receiving selumetinib (including 1 patient 
who had switched from temozolomide treatment after disease progression) versus 1 
patient (1%) in the comparator group.  

Review of clinical laboratory parameters in phase II monotherapy studies identified 
a trend toward increased alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) levels after starting treatment with selumetinib.  An 
increase in serum phosphate was observed in some patients after initiation of 
selumetinib, compared with patients randomised to comparator treatments.There 
was a trend toward a small mean decrease in albumin relative to the comparator.  
No other reports of selumetinib-related changes in laboratory parameters were 
considered to be of clinical relevance at this time.  There was no evidence of 
myelosuppression or renal impairment. 

Adverse events related to visual function have been reported across the programme 
with selumetinib.  Most often there were no specific clinical findings reported from 
patients that underwent ophthalmological evaluation after reporting the AE of visual 
disturbance.  AEs consistent with central serous retinopathy have been reported in a 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
29(118) 
small number of patients receiving treatment with selumetinib, generally in 
combination with other anti-cancer agents.  

There have been reports of pneumonitis-type events in a small number of patients 
receiving treatment with selumetinib. An association with selumetinib has not been 
established. An algorithm for investigation of dyspneoa is provided in Appendix G: 
"Guidance for Management of Adverse Events in Studies of Selumetinib." 

Weakness of neck extensor muscles in conjunction with creatine phosphokinase 
(CPK) increases (reversible on treatment interruption) have been reported in 3 out 
of 54 patients with uveal melanoma receiving selumetinib 75 mg twice daily in one 
non-AstraZeneca sponsored study. Increases in CPK levels have been recorded in a 
small number of patients receiving treatment with selumetinib. CPK elevations are 
present in some patients with muscle symptoms, although asymptomatic elevations 
have also been reported. A relationship between selumetinib and elevated CPK 
levels or myopathy has not been established. 
In the DTC pilot study described in Section 1.1.5.2 (Ho et al 2012), where 20 metastatic 
thyroid cancer patients were treated with a 4 week course of selumetinib 75 mg twice daily, all 
events attributed to selumetinib were Grade 1 or 2, and included fatigue (80%), maculo-
papular rash (70%), acneiform rash (25%), elevation in AST (70%; all Grade 1), elevation in 
ALT (45%; all Grade 1), diarrhea (45%), nausea (40%), limb edema (30%), oral mucositis 
(35%), constipation (20%), hypoalbuminemia (15%), decreased white blood cell count (15%), 
face edema (10%), scalp pain (10%), decreased platelet count (1 patient; Grade 1), eye 
disorder (1 patient; Grade 1 consisting of visual halos and slight blurriness that resolved after 
therapy stopped), hypertension (1 patient; Grade 1), periorbital edema (1 patient; Grade 1), 
and vomiting (1 patient, Grade 1).  One patient who was treated with RAI was subsequently 
diagnosed with myelodysplastic syndrome 51 weeks after RAI administration which 
subsequently evolved into acute leukaemia (this was determined to be unrelated to selumetinib 
and likely related to cumulative RAI toxicity as well as previous external beam radiation 
therapy).  All adverse events were readily managed with supportive mediations and were 
reversible upon discontinuation of selumetinib.  None of the 20 patients required dose delays 
or reductions due to selumetinib toxicity.   
In the only other study to specifically investigate selumetinib in differentiated thyroid cancer 
patients (the phase II study of 100 mg bid selumetinib, previous mix-and-drink formulation) in 
39 patients with RAI-refractory differentiated metastatic thyroid cancer (Hayes et al 2012). In 
these patients with RAI-refractory disease, common drug-related AEs included rash (77%), 
fatigue (49%), diarrhea (49%), and peripheral oedema (36%).  Grade 3 and 4 AEs were 
consistent with those across the selumetinib program and also included rash (18%), fatigue 
(8%), diarrhea (5%) and peripheral oedema (5%).  Twelve patients required dose reductions 
for reported AEs across the length of the study (the duration of treatment was greater than 16 
weeks for 69% of patients).  Six patients (15%) discontinued treatment due to adverse events. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
30(118) 
A study of selumetinib in combination with radiation in patients with non-small cell lung 
cancer has recently been opened but no safety or efficacy results are yet available from this 
study.  
Selumetinib is not mutagenic or clastogenic in vitro but produced increases in micronucleated 
immature erythrocytes in mouse bone marrow micronucleus studies.  Investigatory studies 
show that this is predominantly via an aneugenic mechanism which is consistent with 
disruption of normal spindle function as a consequence of the known pharmacological action 
of a MEK inhibitor.  With selumetinib Hyd-Sulfate, a NOEL of 24 mg/kg/day (for 2 days) 
was established for induction of micronuclei, with plasma exposures significantly above those 
observed in cancer patients at the maximum tolerated dose of 75 mg twice daily.  This 
suggests that selumetinib will have little potential to cause aneugenicity in dividing cell 
populations in patients at the proposed clinical dose.  Thus, any additional aueugenic risk from 
a 5 week course (maximum 43 days) of twice daily 75 mg selumetinib dosing in this 
potentially curative patient setting, is considered to be negligible in comparison with the 
known and more substantial risk from radiation exposure following a therapeutic dose of 131I 
(100 mCi) that patients will receive as part of standard of care.    
In summary, selumetinib has been shown to have an acceptable profile of side effects, in an 
extensive safety database for a compound at this stage of development.   
Further details regarding the safety profile of selumetinib can be found in the Investigator 
Brochure. 
1.2 
Research hypothesis 
Pre-treatment with selumetinib enhances the uptake of radioactive iodine in differentiated 
thyroid cancer, resulting in a greater incidence of complete remission after adjuvant RAI 
therapy in patients at high risk of primary treatment failure. 
1.3 
Rationale for conducting this study 
Unfortunately a significant proportion of thyroid cancer patients are not cured by their initial 
surgery and RAI therapy. This is often due to the inability of their cancer cells to adequately 
incorporate RAI (due to reduced expression of NIS). In such cases, repeated administration of 
RAI may be given (for RAI avid disease) with the aim of inducing remission and curing their 
disease. This outcome however is not guaranteed, and patients who subsequently develop 
refractory metastatic disease have a much poorer prognosis and may eventually succumb to 
their disease; at least one third of patients who develop metastatic disease have no or very low 
uptake and are thus not amenable to further RAI treatment.  There is thus an urgent need for a 
medicine that can enhance the effectiveness of initial RAI treatment and increase the 
probability of achieving remission, thereby preventing more patients from developing distant 
metastatic disease.  


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
31(118) 
1.4 
Benefit/risk and ethical assessment 
It is clear from the Investigator-sponsored study (Ho et al 2012), that a short course of 
selumetinib prior to RAI therapy, is effective in enhancing RAI uptake, reducing tumour 
marker (Tg) levels, and reducing tumour size in heavily pre-treated patients with documented 
RAI-refractory disease. Most patients in the pilot clinical study had numerous metastatic 
lesions, some of which were refractory to RAI at baseline and some of which were partially 
RAI avid at baseline.  Importantly, selumetinib pre-treatment not only restored RAI uptake in 
previously refractory lesions, but also increased RAI uptake in the majority of partially avid 
lesions (typically by more than 100% compared to the baseline value; 3- to 7-fold increases in 
maximum SUVs in such lesions were consistently observed). This pilot data not only supports 
the preclinical hypothesis that inhibiting the MAPK pathway can convert non-RAI avid 
lesions to RAI avid tumours, but also demonstrates that iodine uptake in previously iodine 
sensitive lesions can be significantly increased with selumetinib.  This observation broadens 
the potential clinical applicability of this approach beyond just RAI-refractory thyroid cancer, 
to the use of selumetinib and RAI as part of upfront adjuvant treatment of RAI-naïve and 
susceptible DTC.  
The potential benefit to patients in this study is therefore high, with an increased chance of 
complete remission. The toxicity risk from a short course (approximately 5 weeks) of 
selumetinib treatment has been carefully considered for this potentially curative population; 
the side effect profile of selumetinib in the short timeframe (maximum 6 weeks of exposure) 
is considered to be predictable, manageable and reversible (mainly rash and fatigue). The long 
term risk of secondary malignancies associated with RAI is considered low from a single 
100 mCi dose, as these are rare and more typically develop following cumulative RAI 
treatments and exposure. Patients under the age of 18 years will be excluded to minimise any 
risk of increased radioactivity exposure in a younger population. The side effect profile of 
both selumetinib and RAI will be monitored over the entire 3 year study duration for each 
patient. 
2. 
STUDY OBJECTIVES 
2.1 
Primary objective 
To compare the efficacy of selumetinib with radioactive iodine therapy (RAI), versus placebo 
with RAI, by assessment of complete remission rate at 18 months post RAI treatment in the 
intention to treat (ITT) study population. Complete remission is defined in Section 6.4.1. 
2.2 
Secondary objectives 
1. 
To compare the efficacy of selumetinib with RAI, versus placebo with RAI, by 
assessment of complete remission rate at 18 months post RAI treatment in a sub-group 
of patients with tumours known to be mutation positive for BRAF or NRAS (defined in 
Section 6.10.1). Complete remission is defined in Section 6.4.1. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
32(118) 
2. 
To compare the efficacy of selumetinib with RAI, versus placebo with RAI by 
assessment of clinical remission rate at 18 months post RAI treatment in the ITT study 
population. Clinical remission is defined in Section 6.4.6. 
3. 
To compare the efficacy of selumetinib with RAI, versus placebo with RAI by 
assessment of clinical remission rate at 18 months post RAI treatment in a sub-group 
of patients with tumours known to be mutation positive for BRAF or NRAS (defined in 
Section 6.10.1). Clinical remission is defined in Section 6.4.6. 
4. 
To assess the safety and tolerability of selumetinib with RAI compared to placebo with 
RAI. 
5. 
To investigate the pharmacokinetics (PK) of selumetinib and N-desmethyl selumetinib 
when administered to patients with differentiated thyroid cancer. 
2.3 
Exploratory objectives 
1. 
To explore subsequent thyroid cancer therapy given to patients who receive  
selumetinib with RAI, or placebo with RAI. 
2. 
To investigate the relationship between selumetinib and/or N-desmethyl selumetinib 
plasma concentrations/exposure and clinical outcomes, efficacy, AEs and/or safety 
parameters. 
3. 
To collect tumour, plasma and serum samples for potential future research on 
biomarkers relevant to DTC and response and resistance to study treatments.  
4. 
To collect and store DNA for future exploratory research into genes/genetic variation 
that may influence response (ie, distribution, safety, tolerability and efficacy) to 
selumetinib or RAI and/or susceptibility to cancer. 
The exploratory analysis will be reported separately from the CSR. 
3. 
STUDY PLAN AND PROCEDURES 
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
standard procedures. 
3.1 
Overall study design and flow chart 
This is a double-blind, randomised, placebo-controlled study to assess the efficacy and safety 
of a short course (approximately 5 weeks) of selumetinib (75 mg, orally twice daily) in 
combination with adjuvant RAI therapy compared to placebo and adjuvant RAI therapy, in 
patients with differentiated thyroid cancer at high risk of primary treatment failure. 
Approximately 228 patients will be randomised 2:1 selumetinib to placebo. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
33(118) 
This will be a multi-centre, international study; it is anticipated that approximately 50 centres 
will recruit patients in South and/or North America and Europe.  
3.1.1 
Treatment Plan 
Following randomisation, patients will take their assigned study treatment (selumetinib or 
placebo) for a period of approximately 5 weeks, twice daily.  Study treatment will begin 
approximately 4 weeks prior to the planned day of RAI therapy. Refer to Table 2 for an 
example study treatment plan. The following treatment criteria must be adhered to: 
1. 
Day 1 of study treatment must occur: 

no earlier than 6 weeks after the patient’s thyroid cancer surgery (their 
last surgery if it was a 2-stage thyroidectomy), and   

no later than 16 weeks after the patient’s thyroid cancer surgery (their last 
surgery if it was a 2-stage thyroidectomy).   
2. 
It is essential that patients remain on study treatment continuously for a minimum 
of 7 consecutive days prior to their planned RAI therapy, on the day of RAI 
therapy, and for 5 consecutive days afterwards.  If necessary, RAI therapy may be 
rescheduled at the discretion of the Investigator until the patient has been on study 
treatment for a minimum of 7 consecutive days beforehand.   
3. 
Study treatment with selumetinib or placebo will typically last for 36 days, but must 
be for no longer than 43 days (this allows the planned RAI to be postponed by up to 
1 week if absolutely necessary).   
4. 
Patients will be required to adhere to a low iodine diet for a period of 1 week before 
their planned RAI adjuvant treatment, until the day after their RAI treatment. Refer 
to Section 5.1.1 and the example diet in Appendix F for further details. 
5. 
For each of the 2 days immediately prior to their planned RAI therapy, patients will 
receive a recombinant human TSH injection (rhTSH, Thyrogen), in order to 
stimulate iodine uptake (refer to Section 5.5.4 for details). 
6. 
Following the 2 days of rhTSH injections, patients will receive their planned RAI 
therapy the immediate next day (refer to Section 5.5.4 for further RAI dosing 
information).   
7. 
Twice daily dosing of selumetinib/placebo will continue for 5 days following RAI 
therapy (Day 36 will typically be the last day of study treatment, but this can extend 
to Day 43 if necessary). 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
34(118) 
Table 2 
Example study treatment plan  
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Sunday 
Day 1 
X 
Day 2 
X 
Day3 
X 
Day 4 
X 
Day 5 
X 
Day 6 
X 
Day 7 
X 
Day 8 
X 
Day 9 
X 
Day 10 
X 
Day 11 
X 
Day 12 
X 
Day 13 
X 
Day 14 
X 
Day 15 
X 
Day 16 
X 
Day 17 
X 
Day 18 
X 
Day 19 
X 
Day 20 
X 
Day 21 
X 
Day 22 
X 
Day 23 
X 
Day 24 
X 
Low I diet 
Day 25 
X 
Low I diet 
Day 26 
X 
Low I diet 
Day 27 
X 
Low I diet 
Day 28 
X 
Low I diet 
Day 29 
X 
Low I diet 
Thyrogen 
Day 30 
X 
Low I diet 
Thyrogen 
Day 31 
X 
Low I diet 
RAI 
Day 32 
X 
Low I diet 
Day 33 
X 
Day 34 
X 
Day 35 
X 
Day 36 
X  
last day of 
study 
treatment 
 
Day 38  
(Day 36-41) 
WBS scan 
 (3-10 days 
after RAI 
dose) 
 
 
 
 
 X: Study treatment administration (selumetinib or placebo, twice daily) 
RAI: radioactive iodine therapy (131I) refer to Section 5.5.4.2 for details 
This suggested treatment plan is an example only. The treatments may be planned for different days as long as all 
criteria in Section 3.1.1 are met. 
 
3.1.2 
Follow-up plan 
Following completion of RAI therapy and planned discontinuation of study treatment 
(randomised selumetinib or placebo); patients will be followed up as follows: 
1. 
3-10 days after RAI therapy, patients will undergo a post-therapy whole body RAI 
(131I) nuclear medicine scan to determine where the RAI has localized in the body 
(refer to Section 6.4.4.2 for further detail). 
2. 
Patients will be monitored for TSH and thyroxine (T4) levels as per local standard 
of care (refer to Section 6.4.3.3 for further detail). Note that T4 levels will not be 
collected in the study database. 
3. 
At 9 months (±3 months) following RAI treatment, patients will be assessed for: 
(a) 
TSH-suppressed Tg and Tg antibody levels (TgAb).  Refer to Section 5.9.1.1 
for further details. 


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Edition Number 3 
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(b) 
Neck ultrasound (US). Refer to Section 5.9.1.2 for further details. 
It is important that these assessments are not performed earlier than 6 months after 
RAI treatment.  
4. 
Patients will be assessed for their complete remission status at the primary endpoint 
18 months following their RAI treatment.  A staged approach to the primary 
endpoint assessments will be used in this study in order to determine remission 
status (presence or absence of thyroid cancer), such that each patient may not 
require all assessments. Refer to Section 6.4, Table 4 and Figure 3 for further 
details. The primary endpoint assessments must be started 18 months ± 2 weeks 
following the patient’s RAI dose, and all necessary primary endpoint assessments 
must be completed within an 8 week period. 
Further thyroid cancer therapy (eg, additional surgery, RAI re-treatment, external 
beam radiotherapy or systemic therapy) should only be given during the initial 
18 month follow-up period according to the re-treatment criteria in Section 5.9. Any 
patient that is re-treated in the 18 month period following their RAI therapy will not 
require any primary endpoint assessments performing (they will be determined not 
to be in complete remission for the purpose of the study and will enter standard of 
care follow up, remaining in the study until the 3 year follow up). 
5. 
Following the primary endpoint assessments (or re-treatment), all randomised 
patients will be further followed-up at 3 years following their RAI treatment.  It is 
the responsibility of the study investigator to ensure they conduct follow-up as 
described in this protocol if patients transfer to non-study hospitals, or if patients are 
discharged for routine follow up at other institutions (eg, family doctor or local non-
specialist hospital). 
Assessments planned at each visit are detailed in Table 3, Table 4 and Section 6. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
36(118) 
Figure 1 
Study flow chart  
 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
37(118) 
Table 3 
Study Plan 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Visit Description 
Screening 
Randomi
sation 
On -
treatment 
safety 
visit 
Thyrogen 
RAI 
therapy 
Last day 
of 
treatment 
30 days 
post 
treatment 
4 Month 
safety 
follow up 
9 
Month 
FU 
Primary 
endpoint 
assessmentsa 
27 
Month 
safety 
follow up 
3 Year 
FU 
Protocol 
Section 
Timing 
Day  
-28 to –1 
Day 1 
Day 14 
Days  
29 & 30 
Day 31 
 Day 36 
Week 10 
4 months 
post visit 
5 
9 
months 
post 
visit 5 
18 months 
post visit 5 
27 
months 
post visit 
5 
3 years 
post 
visit 5 
 
Visit Window 
N/A 
N/A 
±1wk 
N/A 
N/A 
N/A 
± 2 days 
± 2 
weeks 
± 3 
months 
Refer to 
Table 4 
± 2 
months 
± 1 
month 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
X 
X 
(Day 29 
or 30) 
 
 
X 
 
 
 
 
 
6.5.6 
Additional screening 
procedures  
X 
 
 
 
 
 
 
 
 
 
 
 
6.2 
Provision of archival 
tumourb 
 
X 
 
 
 
 
 
 
 
 
 
 
6.10.1.
1 
Plasma/serum sample for 
exploratory analysisb 
 
X (pre-
dose) 
 
 
 
 
 
 
 
 
 
 
6.10.2 
Pregnancy test 
X 
 
 
 
X 
 
 
 
 
Xa 
 
 
6.5.9.1 
Optional genetic consent & 
sample (whole blood)  
 
X (pre-
dose) 
 
 
 
 
 
 
 
 
 
 
6.9 
Adverse eventsc 
X 
 
 
 
 
 
 
 
 
 
 
 
6.5.3 
Concomitant medications 
X 
 
 
 
 
 
 
 
 
 
 
 
5.6 
Telephone follow up for 
safetyd 
 
 
 
 
 
 
 
X 
 
 
X 
 
6.5.3 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
38(118) 
Table 3 
Study Plan 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Visit Description 
Screening 
Randomi
sation 
On -
treatment 
safety 
visit 
Thyrogen 
RAI 
therapy 
Last day 
of 
treatment 
30 days 
post 
treatment 
4 Month 
safety 
follow up 
9 
Month 
FU 
Primary 
endpoint 
assessmentsa 
27 
Month 
safety 
follow up 
3 Year 
FU 
Protocol 
Section 
Timing 
Day  
-28 to –1 
Day 1 
Day 14 
Days  
29 & 30 
Day 31 
 Day 36 
Week 10 
4 months 
post visit 
5 
9 
months 
post 
visit 5 
18 months 
post visit 5 
27 
months 
post visit 
5 
3 years 
post 
visit 5 
 
Visit Window 
N/A 
N/A 
±1wk 
N/A 
N/A 
N/A 
± 2 days 
± 2 
weeks 
± 3 
months 
Refer to 
Table 4 
± 2 
months 
± 1 
month 
 
Vital signs (including height 
at screening), weight 
X 
X (pre-
dose) 
X 
X 
(Day 29 
or 30) 
 
 
X 
 
 
 
 
 
6.5.8 
Clinical chemistry 
X 
X (pre-
dose) 
X 
X 
(Day 29 
or 30) 
 
 
X 
 
 
 
 
 
6.5.5 
Haematology 
X 
X (pre-
dose) 
X 
X 
(Day 29 
or 30) 
 
 
X 
 
 
X 
 
X 
6.5.5 
Urinalysis  
X 
 
X 
 
 
 
X 
 
 
 
 
 
6.5.5 
ECGe 
X 
X 
 
Xe (Day 
29 or 30) 
 
 
X 
 
 
 
 
 
6.5.7.2 
ECHO/MUGAf 
X 
 
 
 
 
 
X 
 
 
 
 
 
6.5.7.1 
Ophthalmologic 
examinationf 
X 
 
 
 
 
 
X 
 
 
 
 
 
6.5.9.2 
Selumetinib/placebo dosingg 
 twice daily 
 
 
 
 
 
 
 
 
 
 
 
 
5.5.2 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
39(118) 
Table 3 
Study Plan 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Visit Description 
Screening 
Randomi
sation 
On -
treatment 
safety 
visit 
Thyrogen 
RAI 
therapy 
Last day 
of 
treatment 
30 days 
post 
treatment 
4 Month 
safety 
follow up 
9 
Month 
FU 
Primary 
endpoint 
assessmentsa 
27 
Month 
safety 
follow up 
3 Year 
FU 
Protocol 
Section 
Timing 
Day  
-28 to –1 
Day 1 
Day 14 
Days  
29 & 30 
Day 31 
 Day 36 
Week 10 
4 months 
post visit 
5 
9 
months 
post 
visit 5 
18 months 
post visit 5 
27 
months 
post visit 
5 
3 years 
post 
visit 5 
 
Visit Window 
N/A 
N/A 
±1wk 
N/A 
N/A 
N/A 
± 2 days 
± 2 
weeks 
± 3 
months 
Refer to 
Table 4 
± 2 
months 
± 1 
month 
 
PK blood samplesh 
 
X 
 
Xh (Day 
29 or 30) 
 
 
 
 
 
 
 
 
6.7 
Low iodine dieti 
 
 
 
X 
X 
 
 
 
 
Xa 
 
 
5.1.1 
Thyrogen injection 
 
 
 
Xx2 
(Day 29 
and 30) 
 
 
 
 
 
Xx2a 
 
 
5.5.4.1 
131I (RAI) treatment  
single 100 mCi dose 
 
 
 
 
X 
 
 
 
 
 
 
 
5.5.4.2 
131I 5 diagnostic dose for 
WBS 
single 5 mCi dose 
 
 
 
 
 
 
 
 
 
Xa 
 
 
5.5.4.2 
131I nuclear medicine WBS 
scan 
 
 
 
 
 
Xj 
 
 
 
Xa 
 
 
6.4.4.2 
Re-treatment assessmentk 
 
 
 
 
 
 
 
 
X 
X 
 
X 
5.9 
Blood sample for TSH  
 
 
 
 
 
 
 
 
X 
X  
 
 
6.4.3.3 
Blood sample for 
suppressed Tg 
 
 
 
 
 
 
 
 
Xn 
X 
 
 
6.4.3.1 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
40(118) 
Table 3 
Study Plan 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Visit Description 
Screening 
Randomi
sation 
On -
treatment 
safety 
visit 
Thyrogen 
RAI 
therapy 
Last day 
of 
treatment 
30 days 
post 
treatment 
4 Month 
safety 
follow up 
9 
Month 
FU 
Primary 
endpoint 
assessmentsa 
27 
Month 
safety 
follow up 
3 Year 
FU 
Protocol 
Section 
Timing 
Day  
-28 to –1 
Day 1 
Day 14 
Days  
29 & 30 
Day 31 
 Day 36 
Week 10 
4 months 
post visit 
5 
9 
months 
post 
visit 5 
18 months 
post visit 5 
27 
months 
post visit 
5 
3 years 
post 
visit 5 
 
Visit Window 
N/A 
N/A 
±1wk 
N/A 
N/A 
N/A 
± 2 days 
± 2 
weeks 
± 3 
months 
Refer to 
Table 4 
± 2 
months 
± 1 
month 
 
Blood sample for TgAb 
X 
 
 
 
 
 
 
 
X 
X 
 
 
6.4.3.4 
Blood sample for rhTSH-
stimulated Tg 
 
 
 
 
 
 
 
 
 
Xa 
 
 
6.4.3.2 
Neck ultrasound 
Xl 
 
 
 
 
 
 
 
X 
X 
 
 
6.4.4.1 
Neck MRI 
Xl 
 
 
 
 
 
 
 
 
Xa 
 
 
6.4.4.3 
Chest CT without contrast  
Xl 
 
 
 
 
 
 
 
 
Xa 
 
 
6.4.4.4 
Final follow-up assessment 
of clinical status 
 
 
 
 
 
 
 
 
 
 
 
X 
6.4.8 
Biopsy/FNA for disease 
confirmation 
 
 
 
 
 
 
 
 
Xm 
Xm 
 
 
6.4.4.5 
Tumour biopsy on 
progression (optional) 
Optional sample on disease progression (for example, if the patient is re-treated for persistent or recurrent thyroid cancer, or has further surgery). 
Note that both a plasma and serum sample for exploratory analysis should also be taken on disease progression. 
6.10.3 
6.10.2 
Study Plan Table 3 Footnotes 
a Refer to Table 4 and Section 6.4.2. 
b  Provision of these samples is mandatory in this study. Samples should also be obtained on progression (refer to Section 6.10.2). 
c All AEs/SAEs should be collected from the day of consent until 30 days following the last dose of study treatment. From then on, all SAEs (regardless of 
causality), and all AEs related to either RAI, or the combination of RAI and study treatment, should be collected until the last study visit 3 years 
following the patient’s RAI dose. The same AE collection scheme applies for any re-treated patient.  


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
41(118) 
d The Investigator (or delegate) is required to contact the patient by telephone to follow up for any safety information (according to the collection scheme 
detailed in Section 6.5). For re-treated patients, safety follow-up should continue according to the protocol-scheduled visits, but may be collected by 
telephone if necessary at each visit (refer to Section 5.9). 
e Single ECG assessments 1-2 hours following the first dose on Day 1 and Day 29 or Day 30 of study treatment. A single ECG assessment is also required 
whenever an ECHO/MUGA is performed, on any cardiorespiratory AE, and for premature discontinuation. 
f These assessments must also be performed on symptomatology according to the relevant protocol section. 
g Study treatment must be initiated no earlier than 6 weeks after the patient’s thyroid cancer surgery, and no later than 16 weeks after the patient’s thyroid 
cancer surgery (their last surgery if it was a 2-stage thyroidectomy). 
h Each patient will be asked to contribute 8 PK blood samples, one from each of the four pre defined time windows on both Day 1 and Day 29 or Day 30.  The 
Day 29 or Day 30 PK blood samples may be taken earlier, from Day 22 onwards of study treatment if preferred, but it is essential that all PK blood 
samples are collected before the RAI dose is administered. (a) Pre-dose (within 15 minutes of dosing), (b) between 15 minutes and 1 hour post-dose, (c) 
between 1.5 and 2.5 hours post-dose, and (d) between 3 and 8 hours post-dose. 
i  All patients must adhere to a low iodine diet (an example diet is provided in Appendix F). 
j The post-RAI WBS may be performed any time from 3-10 days following the patient’s RAI dose (thus it does not have to be on the same day as the last dose 
of study treatment). 
k The re-treatment assessment will establish whether the patient has received any further treatment for thyroid cancer. Refer to Section 5.9 for the study 
criteria for re-treatment in the initial 18 months following the patient’s RAI dose. 
l The post-operative imaging assessments must be performed no sooner than 4 weeks post-surgery, and after all other screening assessments have been 
performed (ie, they should not be performed for any patient that is otherwise ineligible).  
m Only if required (refer to Section 6.4.4.5) 
n A repeat sample for suppressed Tg may be required 2-4 weeks later, refer to Section 5.9.1.1. 
For imaging data that is required to be sent to the central imaging CRO at any point in the study refer to Section 6.4.4.5. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
42(118) 
Table 4 
Study Plan for the 18 month Primary Endpoint Assessments 
A staged approach to the primary endpoint assessments will be used in this study in order to determine remission status (absence of 
thyroid cancer), such that each patient may not require all assessments. Full details are outlined in Section 6.4.2. 
 
Stage 1 
Stage 2 
Stage 3 
Protocol Section 
Time window 
Stage 1 assessments must be started 18 months ± 2 weeks following the patient’s RAI 
dose, and all necessary primary endpoint assessments must be completed within an 8 
week period. 
6.4.2 
Thyroid cancer re-treatment assessmenta 
Xa 
 
 
5.9 
Suppressed Tg  
X 
 
 
6.4.3.1 
TSH 
X 
 
 
6.4.3.3 
TgAbb 
Xb 
Xb 
 
6.4.3.4 
Neck USf 
X 
 
 
6.4.4.1 
Biopsy or FNAd 
Xd 
 
 
6.4.4.5 
Haematology 
X 
 
 
6.5.5 
Low iodine diete 
 
Xe 
 
5.1.1 
Thyrogen injectionc 
 
X x 2c 
 
5.5.4.1 
Stimulated Tgc 
 
Xc 
 
6.4.3.2 
Pregnancy test 
 
X 
 
6.5.9.1 
Diagnostic 5mCi 131I dosec 
 
Xc 
 
5.5.4.2 
WBS (nuclear medicine scan)c, f 
 
Xc 
 
6.4.4.2 
Neck MRI with contrastf 
 
 
X 
6.4.4.3 
Chest CT without contrastf 
 
 
X 
6.4.4.4 
Selumetinib/RAI-related AE/SAEs  
 
 
 
6.5.3 
 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
43(118) 
Footnotes for Table 4: Study Plan for the 18 month Primary Endpoint Assessments 
a Patients that have been re-treated for thyroid cancer between their initial RAI dose and the primary endpoint assessments 18 months later (refer to Section 
5.9 for re-treatment criteria), will not have any primary endpoint assessments performed, they will remain in the study and enter standard of care follow 
up according to local practice. They should still be followed up for safety information at 18 m, 27 m and 3 years following their initial RAI dose. 
b For decision making purposes at any time in the study, standardised central analysis results must be used. If the stage 1 blood sample is positive for TgAb, 
but the stage 2 blood sample is negative for TgAb, then a third blood sample 10 days later (± 3 days) is required to confirm absence of TgAb.  
c Patients will receive 2 Thyrogen injections on consecutive days (day 1 and 2), followed by a diagnostic dose (5mCi) of 131I on either day 2 or day 3, and a 
blood draw for stimulated Tg central assessment and WBS both on day 5.  
d Only if required to prove absence of disease for suspicious lesions (refer to Section 6.4.4.5). 
e Patients will be required to adhere to a low iodine diet for a period of 1 week before their planned RAI adjuvant treatment, until the day after their RAI 
treatment. Refer to Section 5.1.1 and the example diet in Appendix F for further details. 
f For imaging data that is required to be sent to the central imaging CRO refer to Section 6.4.4.5.


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
44(118) 
3.2 
Rationale for study design, doses and control group 
This study is designed to determine the efficacy of a 5-week course of selumetinib or placebo, 
and adjuvant RAI therapy, by assessing the rate of complete remission at 18 months post-RAI 
therapy.  
The dose and duration of selumetinib treatment in this study (75 mg twice daily for 5 weeks) 
is selected to be consistent with the pilot study, which has previously demonstrated enhanced 
RAI uptake following selumetinib treatment, reduction in Tg levels, and reduced tumour size 
following RAI therapy, in patients with RAI-refractory metastatic thyroid cancer (Ho et al 
2012).  In addition to the effects of selumetinib on the sodium iodine transporter (refer to 
Section 1.1.5.1), selumetinib may also increase levels of thyroid peroxidase and thyroglobulin 
in any remaining thyroid cells. These proteins are required to organify and retain iodide in 
thyroid cells, thus facilitating greater retention of 131I, and a higher dose of radiation to cancer 
cells. For this reason, patients will remain on selumetinib treatment for 5 days after receiving 
the therapeutic dose of RAI. 
Since RAI is the standard of care for this patient population, the selumetinib/RAI treatment 
group will be compared to a placebo/RAI control group for all study endpoints. 
The population who will participate in this study will be patients with differentiated thyroid 
cancer at high risk of primary treatment failure that would routinely require RAI adjuvant 
therapy as standard of care. This risk-stratified population has been selected because it is 
known that they are at an increased risk of failing to achieve remission following standard 
initial therapy, and therefore require more effective treatment strategies (refer to Section 
1.1.3). This study is intended to be an adjuvant therapy trial for patients without known 
structural persistent disease; patients with known distant metastases at screening will be 
excluded in order to minimise heterogeneity of the efficacy recorded.  
A secondary efficacy endpoint will be assessed in patients with tumours carrying BRAF or 
NRAS mutations, as these are known to constitutively activate the MEK signalling pathway. 
Treatment with a MEK inhibitor may thus be hypothesised to deliver a greater treatment effect 
in these patients. However, the pathway can be activated in many ways such that these 
patients are not likely to be the only population to benefit. Incorporation of a genetically 
predefined study population enables this hypothesis to be examined (mutation analysis of 
samples to identify the genetically predefined study population will be performed post-
randomisation, and prior to data base lock for the primary endpoint data analysis). 
Enhancing RAI uptake into thyroid cancer cells has the potential to increase the incidence of 
complete remission following RAI treatment. It has been shown that the incidence of 
complete remission following initial RAI treatment correlates with long-term outcome, and if 
complete remission has not been achieved, further treatment is frequently administered 
(Castagna et al 2011, Tuttle et al 2010).    
A study has retrospectively evaluated the time to nadir Tg in 299 patients who did not receive 
additional therapy after total thyroidectomy and RAI (Padovani et al 2012).  This patient 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
45(118) 
population includes both patients with no evidence of disease (remission) and patients with 
low level disease who are being observed (median follow up time is 7 years).  Figure 2 
illustrates that 94% of the 223 patients with no evidence of disease achieved a suppressed Tg 
level of < 1 ng/mL (the biochemical component of remission) by 18 months after initial RAI 
therapy. Therefore, it is expected that most patients who are likely to achieve remission in 
both arms will have done so by this time (for the purpose of this study both biochemical and 
structural absence of disease will be assessed).  Longer follow-up would not be expected to 
change the conclusions regarding an efficacy difference between the two study arms. In 
patients with similar characteristics to those planned in this study, a similar pattern and extent 
of Tg decline is also seen (Tuttle RM, unpublished sub-analysis of data from Padovani et al 
2012).  Previous studies have used time-points ranging from 8 to 24 months to assess 
remission rates after primary treatment of surgery and RAI (Castagna et al 2011, Tuttle et al 
2010, Vaisman et al 2012).   
Taking all the data into consideration, the incidence of complete remission at 18 months 
following initial RAI therapy has been selected as the primary endpoint for the proposed 
study.  Each randomised patient will be followed beyond their 18 month primary endpoint 
assessment, until 3 years after their RAI treatment, in order to further assess both the clinical 
status of patients, and the safety profile of selumetinib and RAI beyond the primary analysis 
(refer to Section 6.4.8).   
Figure 2 
Time course to achieving a suppressed Tg<1 ng/mL in patients 
receiving total thyroidectomy and RAI therapy 
 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
46(118) 
4. 
PATIENT SELECTION CRITERIA 
Investigator(s) should keep a record, (eg, patient screening log), of patients who entered pre-
study screening.  
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule. 
4.1 
Inclusion criteria 
For inclusion in the study patients should fulfil the following criteria: 
1. 
Provision of informed consent prior to any study specific procedures. The main 
study consent will include mandatory consent to provide a sample of archival 
tumour material.  
2. 
Males and females aged 18 years or above. 
3. 
Patients with histologically or cytologically confirmed follicular cell derived 
differentiated thyroid cancer including papillary thyroid cancer and all variants, 
follicular thyroid cancer and all variants, and poorly differentiated thyroid cancer.  
4. 
Note: Patients with a diagnosis of Hürthle cell carcinoma should be excluded. These 
are defined as having an invasive tumour composed of >75% of oncocytic (Hürthle) 
cells lacking the nuclear features of papillary carcinoma, tumor necrosis and marked 
mitotic activity. Patients with oncocytic (Hürthle cell variants) of papillary thyroid 
carcinoma defined as a tumour composed of a majority of oncocytic (Hürthle) cells 
having the nuclear features of papillary carcinoma are eligible to participate. 
5. 
Patients presenting with any one of the following staging categories post-surgery: 
(a) 
Primary tumour greater than 4 cm  
(b) 
Primary tumour of any size with gross extrathyroidal extension outside the 
thyroid gland (T4 disease) 
(c) 
N1a or N1b disease with at least 1 lymph node  1 cm 
(d) 
N1a or N1b disease involving 5 or more lymph nodes (of any size) 
Note: Patients with known metastatic disease at screening will be ineligible for this 
study as per the exclusion criteria. 
6. 
Patients must have had a one or two-stage total thyroidectomy with therapeutic neck 
dissection of any clinically apparent metastatic lymph nodes (levels I to VII of the 
lateral and central neck). All known tumour must have been resected.  


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
47(118) 
Note, the optimal surgical procedure is based on the findings from preoperative 
ultrasound, to identify the extent of lymph node metastases and thereby facilitate 
compartment-oriented neck dissection for complete surgical removal of all gross 
disease. Prophylactic neck dissection is not required or encouraged, but may be 
performed at the discretion of the treating surgeon. As the surgical procedure(s) will 
have been performed before study consent, any patient for whom a total 
thyroidectomy cannot be verified must be excluded from the study (note that 
patients having undergone a robotic or endoscopic thyroidectomy, or any other 
novel or remote access surgical technique must also be excluded). For patients who 
have had a two-stage thyroidectomy, the second surgical procedure must have taken 
place no later than 12 weeks after the first procedure, otherwise the patient is not 
eligible. 
7. 
Patients must have all of the following post-operative assessments performed no 
sooner than 4 weeks post-surgery (post their last surgery if it was a 2-stage 
thyroidectomy) and the results from each must verify the absence of macroscopic 
disease: 
(a) 
Neck US exam  
(b) 
Neck MRI with contrast 
(c) 
Chest CT without contrast 
Refer to Section 6.3 for further details. These assessments must be performed within 
the 28 day screening period (but ideally after all other screening assessments have 
been performed, ie, they should not be performed for any patient that is otherwise 
ineligible). 
8. 
Patients must be suitable for radioactive iodine therapy. 
9. 
Patients must be suitable for TSH suppression with a goal of 0.5 mIU/L TSH for 
the duration of the study (this may exclude some patients with cardiac conditions or 
osteoporosis). 
10. 
Patients must be willing and able to start study treatment within 16 weeks of their 
thyroid cancer surgery (their last surgery if it was a 2-stage thyroidectomy). Note 
that study treatment must not be initiated within 6 weeks of the patient’s last 
surgery. 
11. 
WHO or ECOG Performance Status 0 or 1. 
12. 
Females must: 
(a) 
be using adequate contraceptive measures (refer to Section 5.1.2),   


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
48(118) 
(b) 
not be breast feeding (breast feeding must be discontinued in order to 
participate in this study), 
(c) 
have a negative pregnancy test prior to the start of dosing if they are of child-
bearing potential, 
(d) 
or must have evidence of non-child-bearing potential by fulfilling one of the 
following criteria at screening: 
(i) 
Post-menopausal defined as aged more than 50 years and amenorrhoeic 
for at least 12 months following cessation of all exogenous hormonal 
treatments. 
(ii) Women under 50 years old will be considered postmenopausal if they 
have been amenorrheic for at least 12 months following cessation of 
exogenous hormonal treatments, and with LH and FSH levels in the post-
menopausal range for the institution. 
(iii) Documentation of irreversible surgical sterilisation by hysterectomy 
and/orbilateral oophorectomy and/or bilateral salpingectomy but not tubal 
ligation. 
13. 
Male patients with sexual partners who are pregnant or who could become pregnant 
(ie, women of child-bearing potential) must agree to use acceptable methods of 
contraception until 12 weeks after completing study therapy, or longer if required 
for standard RAI administration restrictions and in accordance with local labels, to 
avoid pregnancy and/or potential adverse effects. 
14. 
Adequate organ function as defined by: 
(a) 
ANC  1.5 x 109/L (1500 per mm3) 
(b) 
Platelets  100 x 109/L (100,000 per mm3) 
(c) 
Hemoglobin  9 g/dL 
(d) 
ALT/SGOT and AST/SGPT < 2.5 X upper limit of normal (ULN). 
(e) 
Bilirubin  1.5 X ULN (with the exception that patients with elevated 
unconjugated bilirubin due to a pre-existing diagnosis of Gilbert’s syndrome 
are eligible for the study) 
(f) 
Serum creatinine clearance > 50mL/min by either Cockcroft-Gault formula 
(see Appendix E) or 24hr urine collection analysis. 
15. 
Patients must be able to swallow selumetinib/placebo capsules for the duration of 
the study treatment period. This may exclude some patients with swallowing 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
49(118) 
dysfunction due to the specific technique required for their thyroid surgery. 
Functional assessment of swallowing ability may be made by the treating 
Investigator. 
4.1.1 
Genetics research study (optional blood sample) 
1. 
For inclusion in the optional genetics research study patients must provide optional 
genetics research informed consent. 
2. 
If a patient declines to participate in the genetics research, there will be no penalty 
or loss of benefit to the patient.  A patient who declines genetics research 
participation will not be excluded from any other aspect of the main study. 
4.1.2 
Biomarkers research study on tumour progression biopsy 
For inclusion in the optional progression tumour sample study, patients must provide optional 
consent for this sample to be obtained. 
If a patient declines to provide consent to obtain optional tumour sample on progression, there 
will be no penalty or loss of benefit to the patient, and the patient will not be excluded from 
any other aspect of the main study. 
4.2 
Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
1. 
Known distant metastatic disease at study entry. Investigators are not required to 
specifically screen patients for distant metastasis beyond their normal Standard of 
Care practices and the protocol-specific post-operative imaging assessments, but 
any patient with known distant metastatic disease at screening must be excluded. 
2. 
Diagnosis of anaplastic thyroid cancer, medullary thyroid cancer, or Hürthle cell 
carcinoma (refer to inclusion criterion 4 for further details on Hürthle cell 
eligibility). 
3. 
Presence of anti-Tg antibodies at screening (as determined by standardised central 
methodology, refer to Section 6.4.3.4). 
4. 
Previous treatment with 131I (RAI) or external beam radiation therapy (EBRT) at 
any time in the past. 
5. 
Any unresolved toxicity  CTCAE Grade 2 from previous anti-cancer therapy 
including the patient’s recent thyroid cancer surgery. 
6. 
Having received an investigational drug during the last 4 weeks prior to first dose of 
study treatment. 


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7. 
Receiving herbal supplements or medications known to be strong inhibitors or 
inducers of the CYP1A2, CYP2C19 and CYP3A4 enzymes unless such products 
can be safely discontinued at least 14 days before the first dose of study medication. 
8. 
Recombinant human TSH (rhTSH, Thyrogen):  
(a) 
Patients with known hypersensitivity to rhTSH will be excluded. 
(b) 
Patients not willing to use rhTSH prior to their RAI treatment will also be 
excluded (ie, patients or clinicians choosing withdrawal of thyroid hormone 
treatment prior to their RAI treatment will be ineligible for this study). 
9. 
Patients requiring medication with high content in iodide (amiodarone), or patients 
receiving IV iodine containing contrast as part of radiographic procedure within the 
last 3 months prior to the planned RAI treatment (unless a urine measurement 
demonstrates that urinary iodide level has returned to normal range earlier than 3 
months following administration of a contrast agent). 
10. 
Patients with clinically significant cardiovascular disease as defined by the 
following:  
(a) 
Uncontrolled hypertension (BP 150/95 despite optimal therapy) 
(b) 
LVEF < 55% measured by echocardiography (or MUGA) 
(c) 
Symptomatic heart failure (NYHA grade II-IV), prior or current 
cardiomyopathy, or severe valvular heart disease 
(d) 
Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite 
medical therapy) 
(e) 
Atrial fibrillation with a ventricular rate >100 bpm on ECG at rest 
(f) 
Acute coronary syndrome within 6 months prior to starting treatment 
(g) 
Mean QTc interval >470 ms  
11. 
Patients with the following ophthalmological findings/conditions: 
(a) 
Intraocular pressure >21 mmHg, or uncontrolled glaucoma (irrespective of 
intraocular pressure) 
(b) 
Current or past history of central serous retinopathy or retinal vein occlusion 
12. 
Patients with a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to agents used in the study. 


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13. 
Any evidence of severe or uncontrolled systemic disease, active infection, active 
bleeding diatheses or renal transplant, including any patient known to have hepatitis 
B, hepatitis C or human immunodeficiency virus (HIV). 
14. 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection or psychiatric illness/social situations that would limit compliance with 
study requirements. 
15. 
Pregnant women will be ineligible (breast feeding should be discontinued if the 
mother is treated with study therapy). 
16. 
Male or female patients of reproductive potential who are not employing an 
effective method of contraception (refer to Section 5.1.2). 
17. 
Refractory nausea and vomiting, chronic gastrointestinal diseases, or significant 
bowel resection that in the Investigator’s opinion would preclude adequate 
absorption of study therapy. 
18. 
History of another primary malignancy within 5 years prior to starting study 
treatment, except for adequately treated basal or squamous cell carcinoma of the 
skin or cancer of the cervix in situ and the disease under study.  
19. 
Clinical judgement by the investigator that the patient should not participate in the 
study. 
20. 
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site). 
21. 
Previous treatment with any MEK or BRAF inhibitor. 
22. 
Previous enrolment or treatment in the present study. 
4.2.1 
Genetics research study (optional blood sample) 
1. 
Exclusion criteria for participation in the optional genetics research component of 
the study: 
(a) 
Previous allogeneic bone marrow transplant 
(b) 
Whole blood transfusion within 120 days of the date of genetic sample collection 
(except for leukocyte depleted blood transfusion, which is allowed) 
For procedures for withdrawal of incorrectly enrolled patients see Section 5.3. 


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5. 
STUDY CONDUCT 
5.1 
Restrictions during the study 
5.1.1 
Low-iodine diet 
Published data and opinion regarding the necessity for a low iodine diet prior to RAI therapy 
or a diagnostic whole body scan is variable.  For the purpose of this study a low iodine diet 
will be mandated in order to standardise patient care and study data as best as possible. 
Compliance to the low iodine diet will not be recorded or assessed, and all randomised 
patients will receive RAI treatment as planned. Refer to Table 2 and the Study Plan (Table 3) 
for further details. An example low iodine diet is provided as Appendix F to this protocol. 
A low iodine diet is necessary at two occasions in the study: 
Prior to RAI adjuvant treatment 
All patients must be willing to adhere to the low iodine diet for a period of 1 week before their 
planned RAI adjuvant treatment, until the day after their RAI therapy. 
Prior to the primary endpoint Stage 2 assessments 
All patients must be willing to adhere to the low iodine diet for a period of 1 week before the 
diagnostic 131I dose used prior to the primary endpoint WBS assessment (131I nuclear medicine 
scan), until the diagnostic WBS assessment is completed. This is only relevant for patients 
who pass Stage 1 primary endpoint assessments (refer to Section 6.4.2). 
5.1.2 
Other study restrictions 
The following restrictions also apply while the patient is receiving selumetinib or placebo:  
1. 
Female patients of child-bearing potential will be required to use reliable methods 
of contraception until 4 weeks after the last dose of selumetinib/placebo or longer if 
required for standard RAI administration restrictions and in accordance with local 
labels.  Male patients will be required to use reliable methods of contraception until 
12 weeks after the last dose of the last study treatment, or longer if required for 
standard RAI administration restrictions and in accordance with local labels.  
Reliable methods of contraception should be used consistently and correctly.  
Acceptable methods include implants, injectables, combined oral contraceptives 
(which must all be combined with barrier methods of contraception), some IUDs 
and vasectomised partner.  Sexual abstinence is also an acceptable method of 
contraception according to ICHM3. 
2. 
Fasting restrictions for the study are described in Section 5.5.2.   
3. 
Patients should avoid excessive sun exposure and use adequate sunscreen protection 
if sun exposure is anticipated. 


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4. 
Patients should avoid large amounts of grapefruit and Seville oranges (and other 
products containing these fruits eg, grapefruit juice or marmalade) during the study 
treatment period. 
5. 
Selumetinib capsules contain D-- Tocopheryl polyethylene glycol 1000 succinate 
(TPGS, a water-soluble form of vitamin E) as an excipient.  Patients should not 
therefore 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.  The maximum dose of vitamin E patients may receive from selumetinib 
is approximately 210 mg/day. The concomitant intake of excessive 
(supratherapeutic) doses of vitamin E should be avoided. High doses of vitamin E 
have been reported to potentiate the anticoagulant activity of coumadins such as 
warfarin. Patients who are taking coumadin anticoagulants should increase the 
frequency of assessment of anticoagulation, such as INR measurements, upon 
initiation of dosing with study treatment. 
6. 
Permitted and excluded antiemetic medications in this study are described in 
Section 5.6.   
7. 
Permitted and excluded medications for management of skin toxicities (eg, rash) are 
described in Appendix G: “Guidance for Management of Adverse Events in Studies 
of Selumetinib.” All patients will be given prophylactic provision of emollient 
cream to take home and to start using when starting study treatment. 
8. 
Unless patients require re-treatment, they should not be enrolled in other studies 
evaluating novel therapies for thyroid cancer for the entire study duration. 
5.2 
Patient enrolment, randomisation and initiation of investigational 
product 
The Principal Investigator or delegate will: 
1. 
Obtain signed informed consent from the potential patient before any study specific 
procedures are performed. 
2. 
Determine patient eligibility. See Sections 4.1 and 4.2 
3. 
Call IVRS/IWRS to assign the eligible patient a unique enrolment number 
(beginning with ‘E#’), and randomisation code (subject number).  Randomisation 
codes will start at 001 and go up. 
Randomisation codes will be assigned strictly sequentially by IVRS/IWRS as patients are 
eligible for randomisation.  
If a patient withdraws from the study, then his/her enrolment/randomisation code cannot be 
reused. 


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If a patient withdraws from the study after they have been enrolled or have received study 
treatment then they cannot re-enter the study. 
5.2.1 
Procedures for randomisation 
Patients who satisfy all the entry criteria will be centrally assigned by the IVRS/IWRS, 
according to the randomisation scheme generated by the Biostatistics Group, AstraZeneca, to 
selumetinib or placebo in a ratio of 2:1.  
Every effort should be made to minimise the time between randomisation and starting 
treatment.  Patients must not be randomised unless all eligibility criteria have been met. 
IVRS/IWRS will be used for allocation of enrolment number, allocation of randomisation 
number, study medication assignment, discontinuation from study treatment, emergency code 
breaks and study drug shipment confirmation.   
5.3 
Procedures for handling patients incorrectly enrolled, randomised 
or initiated on investigational product 
Patients who fail to meet the inclusion/exclusion criteria should not, under any 
circumstances, be enrolled or receive study medication.  There can be no exceptions to this 
rule. Patients who are incorrectly enrolled but are not yet randomised or initiated on treatment 
should be withdrawn from the study. 
Where patients that do not meet the inclusion and/or exclusion criteria, are enrolled in error, or 
incorrectly started on treatment, or where patients subsequently fail to meet the study criteria 
post initiation, the investigator should inform the AstraZeneca Physician immediately.  
The AstraZeneca Physician must ensure all such contacts are appropriately documented. 
5.4 
Blinding and procedures for unblinding the study  
5.4.1 
Methods for ensuring blinding 
The active and placebo capsules will appear identical and presented in the same packaging to 
ensure blinding of the medication.  Medication will be labelled using a unique material pack 
code which is linked to the randomisation scheme.  IVRS/IWRS will allocate randomisation 
numbers sequentially when sites call IVRS/IWRS to randomise an eligible patient.  
IVRS/IWRS will allocate the medication pack code to be dispensed to the patient. 
All patients must remain blinded until after the 18 month primary endpoint data analysis has 
been conducted for the study; most patients will thus remain blinded for longer periods of time 
than their initial 18 month follow up period.  Any patient that is re-treated prior to the 18 
month primary endpoint time-point (refer to guidelines in Section 5.9), must not be unblinded 
until after the primary analysis of 18 month primary endpoint data from all patients in the 
study. 


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The personnel analyzing the PK samples will be unblinded to treatment allocation in order to 
organise the appropriate sample analysis. The treatment allocation information will be kept in 
a secure location until the end of the study. 
Once the 18 month primary endpoint data analysis has been conducted for the study, patients 
may be unblinded for the remaining study follow up. 
5.4.2 
Methods for unblinding the study 
Individual treatment codes, indicating the treatment randomisation for each randomised 
patient, will be available to the investigator(s) or pharmacists from the IVRS/IWRS.  
Procedures for emergency unblinding will be described in the IVRS/IWRS user manual that 
will be provided to each centre. 
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomisation. The 
investigator documents and reports the action to AstraZeneca, without revealing the treatment 
given to patient to the AstraZeneca staff. 
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational product and that potentially require 
expedited reporting to regulatory authorities.  Treatment codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each individual 
patient have been made and documented. 
5.5 
Treatments 
5.5.1 
Identity of investigational product(s) 
Investigational product 
Dosage form and strength 
Manufacturer 
Selumetinib 
 
25 mg Hyd-Sulfate capsule 
AstraZeneca 
Placebo to match selumetinib 
Capsule  
AstraZeneca 
 
5.5.2 
Doses and treatment regimens 
Patients will be randomised on a 2:1 basis, via IVRS/IWRS, to receive either selumetinib 
75 mg twice daily, or matching placebo. 
Patients will be instructed to take 3 capsules orally on an empty stomach (no food or drink 
other than water for 2 hours prior to dosing and 1 hour after dosing), twice a day 
approximately 12 hours apart according to the Study Plan.  Capsules should be taken with 
water only.  On clinic days when PK samples are scheduled to be taken, dosing should be 
delayed until arrival at the clinic and until the pre-dose PK sample has been taken.  
Selumetinib/placebo will be supplied in bottles of 60 capsules of 25 mg strength. At 
Randomization visit, selumetinib/placebo for the entire treatment period will be dispensed (5 


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bottles). Individual bottles will be dispensed in accordance with the medication identification 
numbers provided by the IVRS/IWRS. 
Day 1 of study treatment must occur within 16 weeks of the patient’s thyroid cancer surgery 
(their last surgery if it was a 2-stage thyroidectomy).   
5.5.3 
Management of study treatment related toxicity 
The immediate management of any adverse event should be according to standard clinical 
practice for that event. Subsequent management of treatment related adverse events should be 
guided by the Investigators’ assessment of causality. 
5.5.3.1 
Selumetinib dose interruption or reduction 
It is essential that patients remain on study treatment continuously for a minimum of 7 
consecutive days prior to their planned RAI therapy, on the day of RAI therapy, and for 5 
consecutive days afterwards.  If necessary, RAI therapy may be rescheduled at the discretion 
of the Investigator until the patient has been on study treatment for a minimum of 7 
consecutive days (as long as the total duration of study treatment does not exceed 43 days, this 
allows the planned RAI to be postponed by up to 1 week if absolutely necessary). 
For all adverse events reported in this study that are considered at least partly causal to 
administration of selumetinib, the following dose modification guidance should be applied.   
Study treatment with selumetinib/placebo should be temporarily interrupted if one of the 
following AEs are observed (and considered causal to study treatment), despite optimal 
supportive care (ie, supportive treatment may be given prior to withholding study treatment): 

Any intolerable adverse event regardless of Grade 

Any adverse events  CTCAE Grade 3 
On improvement of the adverse event to Grade 1 (Grade 2 for rash) or baseline, study 
treatment may be restarted at the original dose or may be reduced at the discretion of the 
investigator. One dose reduction of study treatment to 50 mg twice daily is permitted before 
permanent discontinuation.   

If a further episode of the same AE subsequently requires dose interruption, 
selumetinib may be restarted at the next dose level down on improvement of the 
AE. 

If a different AE subsequently requires dose interruption, selumetinib may be 
restarted at the same dose or at the next dose level down on improvement of the AE.   

Selumetinib should not be re-escalated to an earlier dose level on improvement of 
an AE.  


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The schedule of assessments described in Table 3 should continue relative to Day 1 
in the event of selumetinib dose interruption or reduction. 
Therefore, the dose reduction/adjustment algorithm in the study allows for 2 steps only:  
75 mg twice daily (initial dose) 
 
50 mg twice daily 
 
permanent discontinuation 
All dose delays, reductions and adjustments will be recorded in the appropriate electronic 
Case Report Form (eCRF). 
The guidance above should also be followed for dose interruptions or reductions for adverse 
events of rashes or diarrhoea. Guidance for interruption or reduction of treatment with 
selumetinib may be considered for particular events, as indicated in the algorithms provided as 
a separate study aid in the “Guidance for Management of Specific Adverse Events in Studies 
of Selumetinib” (refer to Section 5.5.3.2).   
5.5.3.2 
Management and investigation of specific selumetinib related AEs 
Recommendations for the management or investigation of the following specific AEs is 
provided in Appendix G: Guidance for Management of Adverse Events in Studies of 
Selumetinib. 

Rash: early initiation of treatment for rash is strongly recommended to minimise the 
duration and severity of the adverse event. All patients should be given prophylactic 
provision of emollient cream to take home and to start using when starting study 
treatment as indicated in the algorithm for management and investigation of rash 
included in Appendix G. 

Visual disturbances: symptoms, including blurred vision, have been reported during 
treatment with selumetinib. Events consistent with central serous retinopathy have 
been reported in a small number of patients receiving treatment with selumetinib, 
generally in combination with other novel targeted anti-cancer agents. AEs of 
central serous retinopathy and retinal vein occlusion have been reported in studies 
of other MEK inhibitors (Lemech & Arkenau 2012). Investigation to determine the 
underlying cause of visual disturbance is recommended. 

Diarrhoea: early initiation of treatment for diarrhoea is strongly recommended to 
minimise the duration and severity of the adverse event. Treatment provision will 
be according to Investigator discretion according to local practice and regulations.  

Dyspnoea: new or worsening dyspnoea has been reported during treatment with 
selumetinib; investigation to determine the underlying cause is recommended. 


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5.5.4 
Additional study drugs 
5.5.4.1 
Thyrogen (rhTSH, thyrotropin alfa for injection) 
Thyrogen use prior to the RAI ablative dose 
Effective use of RAI therapy requires stimulation by TSH in order to maximise RAI uptake by 
thyroid cells. Recombinant human TSH (rhTSH or Thyrogen) will be used to stimulate iodide 
uptake according to the manufacturer’s recommendation (0.9 mg intra-muscular injection for 
2 days immediately prior to the RAI treatment according to the Study Plan Table 3). rhTSH is 
approved for use in routine clinical care as a diagnostic tool to stimulated serum thyroglobulin 
and RAI uptake for diagnostic scanning and as an adjunct to RAI ablation in many countries. 
This allows patients to avoid the hypothyroidism state, since they can maintain their routine 
thyroid hormone supplementation. Patients or clinicians choosing withdrawal of thyroid 
hormone treatment for this purpose will be ineligible for this study. All randomised study 
patients will receive Thyrogen twice prior to their RAI treatment dose. 
Thyrogen use for the primary endpoint assessments (18 months post-RAI) 
For those patients that progress to Stage 2 of the primary endpoint assessments (refer to 
Section 6.4.2),  Thyrogen will be used to stimulate iodide uptake immediately prior to 
administering the diagnostic 131I dose for the primary endpoint WBS assessment.  Patients will 
receive a 0.9 mg intra-muscular Thyrogen injection for two consecutive days.  Refer to 
Section 6.4.2.2 for further details. 
5.5.4.2 
Radioactive iodine (RAI) 
All RAI for the study will be locally provided at each site. 
Therapeutic RAI dose (131I) 
A single oral RAI dose of 100 mCi (3.7 GBq) 131I (+/- 10% at the time of administration) will 
be administered to all patients according to the Study Plan Table 3, according to standard 
practice at each site. 
Diagnostic WBS dose (131I) 
For those patients that progress to Stage 2 of the primary endpoint assessments (refer to 
Section 6.4.2),  a single oral RAI dose of 5 mCi (185 MBq) 131I (+/- 10% at the time of 
administration) will be administered for the primary endpoint WBS (nuclear medicine scan) 
18 months following the ablative treatment dose of RAI. Refer to the Study Plan Table 3, and 
Section 6.4.4.2 for further details. 
5.5.4.3 
Thyroid hormone supplementation (TSH suppression) 
Routine thyroid hormone supplementation (levothyroxine, LT4) is required during the study 
as per standard clinical practice. The purpose of this is both to correct resulting 
hypothyroidism using a dosage appropriate to achieve normal blood levels of thyroid 
hormone, and to inhibit TSH-dependant growth of residual thyroid cancer cells. Thyroid 


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hormone supplementation will be adjusted in individual patients with the aim of achieving 
suppressed TSH levels of <0.5 mIU/L for the duration of the study. 
5.5.5 
Study drug labelling 
Each bottle of selumetinib and matching placebo capsules will be labelled by Pharmaceutical 
Development Supply Chain, AstraZeneca or its designee. 
All labels will comply with good manufacturing practice (GMP) regulations, and will state 
that the drug is for clinical use only or that it is the investigational drug and is to be used by 
qualified investigators only and should be kept out of reach of children. The labels will have 
blank spaces for the site personnel to complete the following at the time of drug dispensing: 
enrolment code, visit number and dispensing date.  
Label text will be translated into local language. 
Each bottle of selumetinib/placebo capsules will have a tear-off portion that will be removed 
at the time of dispensing and attached to the Drug Label Accountability Log.  
5.5.6 
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions.  The 
investigational product label on the bottle specifies the appropriate storage. 
5.6 
Concomitant medications 
The use of antiemetic medication for the prevention of nausea caused by administration of 
radioactive iodine is permitted in this study according to local clinical practice (with the 
exception of aprepitant which is an excluded medication in this study, due to the potential for 
modification of selumetinib exposure via CYP3A4). The administration of any antiemetic 
medication must be recorded in the appropriate sections of the Case Report Form. 
All patients will be given prophylactic provision of emollient cream to take home and to start 
using when starting study treatment as indicated in the algorithm for management and 
investigation of rash included in Appendix G: “Guidance for Management of Adverse Events 
in Studies of Selumetinib.” 
The following treatments/drugs are restricted in this study: 

No other anti-cancer agents, or investigational drugs should be administered whilst 
patients are receiving study medication or are in follow-up in this study (unless the 
patient withdraws from the study, or meets the re-treatment criteria in Section 5.9).   

Patients who are taking coumarin anticoagulants should increase the frequency of 
assessment of anticoagulation, such as INR measurements, during the study 
treatment period with selumetinib/placebo.   


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
The maximum dose of vitamin E patients may receive from selumetinib is 
approximately 210 mg/day. The concomitant intake of excessive (supratherapeutic) 
doses of vitamin E should be avoided in patients receiving the capsule formulation. 

Throughout the study, patients should avoid changes to, or the addition of all other 
concomitant medications, in particular any that may affect the metabolism of 
selumetinib (eg, CYP1A2 or 3A4 inhibitors/inducers), unless considered clinically 
indicated. 
Other medication, which is considered necessary for the patient’s safety and well being, may 
be given at the discretion of the investigator and recorded in the appropriate sections of the 
Case Report Form.  
All concomitant medications will be recorded on the CRF until 30 days after the last dose of 
study treatment, and after this time a study-specific record must be kept of any further 
treatment for thyroid cancer (including surgery), or treatment for RAI-related AEs/SAEs until 
the last study visit for all patients (refer to Section 5.9). 
5.7 
Treatment compliance 
The administration of all study drugs (including investigational products) should be recorded 
in the appropriate sections of the Case Report Form. 
5.7.1 
Accountability 
The study drug provided for this study will be used only as directed in the study protocol. 
The study personnel will account for all study drugs dispensed to and returned from the 
patient. 
Where appropriate facilities and procedures for drug destruction exist, and prior approval from 
the site monitor has been received, site personnel will account for all unused drugs and for 
appropriate destruction. 
Where such facilities do not exist study site personnel/study monitor will return all unused 
drugs to AstraZeneca or its designee according to country rules. 
The AstraZeneca monitors will ensure that all drug-handling procedures at sites are 
appropriate, and that all certificates of delivery and return are completed and signed by the 
site, AstraZeneca, or its delegate, as appropriate.  In addition, the monitor will check that the 
certificate of destruction has been signed by the site, if study drug destruction is performed at 
the site. 
5.8 
Discontinuation of investigational product 
Patients may be discontinued from investigational product (IP) in the following situations: 


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
Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment 

Adverse Event 

Risk to patients as judged by the investigator and/or AstraZeneca 

Severe non-compliance to protocol as judged by the investigator and/or 
AstraZeneca 

A female patient becoming pregnant 
5.8.1 
Procedures for premature discontinuation of a patient from investigational 
product  
A patient that decides to prematurely discontinue investigational product will always be asked 
about the reason(s) and the presence of any adverse events.  If possible, they will be seen and 
assessed by an investigator(s).  Adverse events will be followed up (See Sections 6.5.3 and 
6.5.4), and all study drugs should be returned by the patient.  In this situation, a treatment 
discontinuation visit will be conducted as soon as possible after the patient received the last 
dose of study drug (selumetinb/placebo). A single 12-lead ECG is also required at premature 
discontinuation of treatment. 
If a patient is withdrawn from the study (ie, withdraws consent for follow-up procedures), see 
Section 5.10. 
Collection of all AEs/SAEs will continue until 30 days after the last dose of study drug 
(selumetinib/placebo) for prematurely withdrawn patients. As long as the patient does not 
withdraw consent, follow up in this study will continue as planned. 
Any patient with an AST, ALT or bilirubin value above ULN at time of the last dose of 
selumetinib/placebo should have a further liver chemistry profile (AST, ALT, bilirubin and 
ALP) performed 30 days (±7days) after discontinuation. 
5.9 
Criteria for further thyroid cancer therapy during the study 
5.9.1 
Re-treatment prior to the 18 month primary endpoint assessments 
It is acknowledged that there is variability in thyroid cancer re-treatment clinical practice.  The 
study-specific criteria below are designed to standardise re-treatment prior to the primary 
endpoint assessments for the purpose of this study as best as possible. Thus, further thyroid 
cancer therapy (eg, additional surgery or RAI treatment) prior to the primary analysis of 
complete remission at 18 months post-RAI, must not be administered unless any of the 
following criteria are met.  
Patients meeting the following re-treatment criteria do not have to be re-treated, they can 
instead be followed expectantly without re-treatment at the discretion of the treating 
Investigator. 


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5.9.1.1 
Biochemical disease re-treatment criteria 
The first scheduled post-RAI follow up for serum Tg will be assessed 9 months after the RAI 
dose (± 3 months). Tg assessment for this purpose may take place at any time from 6 months 
after the patient’s RAI treatment (but not before 6 months).   
All biochemical sample analysis for study re-treatment criteria must be performed by 
standardised central laboratory methodology (for further details refer to the Laboratory 
Manual). 
Patients must not be re-treated for thyroid cancer unless any of the following biochemical 
criteria are met: 
1. 
If a serum Tg level  5 ng/mL on central analysis is measured during TSH 
suppression, then a repeat Tg sample must be assessed by central analysis 2-4 
weeks later. The patient must not be re-treated unless both centrally analysed 
samples demonstrate the suppressed Tg level to be 5 ng/mL or higher.   
2. 
If a serum Tg level  10 ng/mL is measured following TSH stimulation, the 
patient may be re-treated (a repeat sample for confirmation is not necessary). Note, 
a stimulated Tg assessment is not part of the study-specific follow up plan for 
patients prior to the 18 month primary endpoint assessments (thus it is not 
recommended or required, and is not included in the Study Plan). However, if a 
stimulated Tg assessment is performed due to local practice, this re-treatment 
criterion applies.  
3. 
If an increase (delta change) in serum Tg level of 3 ng/mL or more is determined 
between two Tg assessments taken 2-4 weeks apart (due to a repeat sample), the 
patient may be re-treated.  
Thus, in the absence of structurally identifiable disease, patients in this study should have 
continued observation without additional thyroid cancer treatment (eg, additional RAI, 
surgery) until the study primary endpoint (18 months after RAI treatment), if the serum Tg 
level remains below 5 ng/mL during TSH suppression, below 10 ng/mL following TSH 
stimulation (if assessed), and is either stable/declining, or rising less than 3 ng/mL between 
samples 2-4 weeks apart.   
Note: If a patient has Tg levels below the above re-treatment criteria, but TgAb are detected 
(ie, the patient is TgAb positive; refer to Section 6.4.3.4), the patient should not be re-treated 
unless new structural disease is detected according to Section 5.9.1.2 (ie, it is recommended 
that patients are not re-treated on the basis of new antibodies alone, in the absence of 
structural disease).  
Unscheduled samples and local analysis 
It is acknowledged that Investigators may wish to also perform their own local biochemical 
analysis according to local standard of care. In general, unscheduled samples that are taken 


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either outside of the visit window specified, or in addition to the scheduled study samples, 
should not be sent for standardised central analysis. Only if such unscheduled local analysis 
leads the Investigator to wish to administer further therapy for thyroid cancer, should a sample 
ideally be sent for central analysis and the above criteria applied before the patient is re-
treated.   
5.9.1.2 
Structural disease re-treatment criteria 
The first post-RAI ultrasound follow up will be assessed 9 months after the RAI dose (± 3 
months). Ultrasound assessment for this purpose may take place at any time from 6 months 
after the patient’s RAI treatment (but not before 6 months).  
Patients must not be re-treated for thyroid cancer unless any of the following structural criteria 
are met: 
1. 
In the absence of any biochemical evidence of thyroid cancer, structural DTC 
should be confirmed prior to re-treatment, by positive histology/cytology from a 
biopsy/FNA of ultrasonographically suspicious lesions or lymph nodes  5 mm in 
the smallest diameter (refer to Section 6.4.4.5).  
2. 
Identification of new distant metastases (these do not need to be confirmed by 
biopsy). Assessment of potential distant metastases is not required, but may be 
performed if clinically indicated at the discretion of the treating Investigator. 
5.9.1.3 
Patient management on study (up to the primary analysis at 18 months post-
RAI) 
At the required follow up visits, the following questions should be answered for each subject: 
1. 
Does the patient have a suppressed Tg  5 ng/mL, a TSH stimulated Tg  10 ng/mL 
or a rising Tg level (increase of 3 ng/mL or more) according to the guidelines in 
Section 5.9.1.1? 
2. 
Does the patient have new loco-regional structural thyroid cancer according to the 
guidelines in Section 5.9.1.2? 
3. 
Does the patient have new distant metastatic lesions according to the guidelines in 
Section 5.9.1.2? 
If the answer is yes to any of the questions, the patient is unlikely to enter remission and may 
be re-treated for thyroid cancer (but does not have to be).  
Full details of any thyroid cancer re-treatment must be recorded on the appropriate eCRF. 
Any re-treated patients will remain in the study and should enter standard of care follow up 
according to local practice until 3 years after their initial RAI therapy (refer to Section 6.4.8).  
Patients who are re-treated prior to the primary endpoint at 18 months post-RAI do not require 
primary endpoint disease assessments performing, however these patients should continue to 


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follow all protocol-scheduled visits for safety (AE/SAE follow-up) as described in the Study 
Plan Table 3 and in Section 6.5.  Patients do not need to attend these follow up visits in person 
(telephone contact is permitted), however when local follow-up visits coincide with protocol-
specified visits, these should ideally be in person where possible. 
If the answer is no to all questions, the patient should continue the study follow-up as per 
protocol without additional thyroid cancer re-treatment. 
5.9.2 
Re-treatment after the 18 month primary endpoint assessments 
Following completion of all assessments for complete remission at the primary endpoint 
18 months post-RAI, patients may receive re-treatment for thyroid cancer as per clinically 
indicated according to local standard of care.  Any re-treated patients will remain in the study 
and should enter standard of care follow up according to local practice until 3 years after their 
initial RAI therapy (refer to Section 6.4.8). 
Full details of any thyroid cancer re-treatment must be recorded on the appropriate eCRF. 
5.10 
Withdrawal from study 
Patients are at any time free to withdraw from study (investigational product and follow-up 
assessments), without prejudice to further treatment (withdrawal of consent).  Such patients 
will always be asked about the reason(s) and the presence of any adverse events.  If possible, 
they will be seen and assessed by an investigator.  Adverse events will be followed up (see 
Sections 6.5.3 and 6.5.4); any remaining study drug should be returned by the patient. 
5.11 
Replacement of patients 
There will be no replacement of randomised patients in this study for any reason. 
6. 
COLLECTION OF STUDY VARIABLES 
6.1 
Recording of data 
A Web Based Data Capture (WBDC) system will be used for data collection and query 
handling.  The investigator will ensure that data are recorded on the electronic Case Report 
Forms as specified in the study protocol and in accordance with the instructions provided. 
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed electronic Case Report Forms.  A copy of the completed 
electronic Case Report Forms will be archived at the study site. 
6.2 
Data collection at enrolment 
The following data will be collected & procedures performed for each patient: 
1. 
Informed consent (to include consent for archival tumour sample provision) 


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2. 
Demography (date of birth, sex, race) 
3. 
Histological/cytological confirmation of thyroid cancer, including post-operative 
disease staging 
4. 
Medical and surgical history  
5. 
Concomitant medications and previous anti-cancer therapy 
6. 
Assessment of WHO or ECOG performance status (refer to Section 6.2.1) 
7. 
Collection of AEs will start after signing the consent form 
8. 
Physical examination  
9. 
Vital signs (resting blood pressure (BP), pulse rate), weight and height 
10. 
Single ECG 
11. 
Blood samples for clinical chemistry and haematology 
12. 
Blood sample for determination of interfering Tg antibodies (central standardised 
analysis) 
13. 
Local derived BRAF and/or NRAS mutation status (where available) 
14. 
Urinalysis (at sites where the local laboratory is able to determine the required 
parameters, see Section 6.5.5) 
15. 
Pregnancy test for female pre-menopausal patients  
16. 
Full ophthalmologic examination, including slit-lamp fundoscopy and intraocular 
pressure examination  
17. 
ECHO or MUGA  
18. 
The following imaging assessments must be performed within the 28 day screening 
period but only after all other screening procedures have confirmed eligibility status 
(refer to Section 6.3): 
(a) 
Neck ultrasound (US) 
(b) 
Neck MRI with contrast 
(c) 
Chest CT scan without contrast 
19. 
Overall assessment of patient eligibility for the study 


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20. 
Upon confirmation of patients’ eligibility, patients will be invited to attend the 
randomisation visit.  Patients must not be randomised unless all eligibility criteria 
have been met. 
21. 
Call interactive voice response system (IVRS)/interactive web response system 
(IWRS) to randomise the patient 
6.2.1 
Performance status definitions 
Performance status will be assessed at screening according to either the WHO or ECOG 
criteria as follows: 
0 = Fully active, able to carry out all pre-disease performance/activities without restrictions 
1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature e.g., light housework, office work 
2 = Ambulatory and capable of self-care, but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 = Completely disabled, cannot carry on self-care, totally confined to bed or chair. 
6.3 
Post-operative imaging assessments for eligibility 
The post-operative imaging assessments of US, neck MRI and chest CT are performed during 
screening to determine study eligibility. These assessments must determine the absence of 
macroscopic persistent disease post-surgery for a patient to be eligible prior to randomisation. 
The post-operative imaging assessments must be scheduled once all other screening 
assessments and eligibility criteria have been verified. 
The screening chest CT procedure must be performed without iodine containing contrast 
agent.  
Eligibility will be determined by the local investigational site. 
Acquisition guidelines for the post-operative imaging assessments will be provided separately 
to this protocol. 
In addition to information recorded on the eCRF for US, the post-operative images for chest 
CT and neck MRI must be collected and sent to the central imaging CRO. 
6.4 
Efficacy  
6.4.1 
Complete remission  
The primary endpoint for this study is complete remission rate at 18 months (following RAI 
treatment). 


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Definition of complete remission: 
Patients will be defined to be in complete remission if all of the following criteria can be 
demonstrated: 
1. 
Serum Tg levels < 1ng/mL during rhTSH stimulation, in the absence of interfering 
Tg antibodies, as assessed by standardised central laboratory analysis. 
2. 
No confirmed evidence of thyroid cancera on neck US, as assessed by investigator 
site review. 
3. 
No confirmed radiological evidence of thyroid cancera, as assessed by blinded 
independent central review.  
4. 
No histopathological evidence of thyroid cancer on FNA/biopsy when performed, 
as assessed by investigator site review. 
5. 
No further thyroid cancer therapy was administered in the first 18 months following 
the initial RAI treatment. 
There are two main components to complete remission: biochemical remission and structural 
remission. Biochemical remission is measured by Tg and structural remission is assessed by 
the imaging assessments US, MRI, CT and WBS in conjunction with biopsy/FNA.  
A staged approach will be taken for performing assessments contributing to the primary 
endpoint, to avoid unnecessary assessments for individual patients who received further 
therapy prior to the primary assessment, and for those patients not in biochemical remission 
(as determined by serum Tg levels in the absence of interfering Tg antibodies). 
aConfirmation of evidence of structural DTC will be either histopathological (from a 
biopsy/FNA; as criterion 4 above), or RAI-avid disease (refer to Section 6.4.4.2). In this 
disease setting, structural abnormalities that are not RAI-avid and do not have confirmed 
histopathology consistent with DTC (ie are not biopsy proven) are considered benign in the 
absence of biochemical DTC. 
6.4.2 
Staged approach to primary endpoint assessments 
Full details of the staged approach to the primary endpoint assessments are outlined below.  
There will be 3 stages of assessments. Patients that have been re-treated for thyroid cancer 
will not have any primary endpoint assessments performed. All patients who have not been re-
treated for thyroid cancer will have stage 1 assessments performed. The decision on whether 
to proceed to stage 2 and 3 assessments for patients that have not been re-treated will be based 
on centrally analysed biochemical data (Tg and TgAb data).  
Sites will receive results from standardised central laboratory analysis of the biochemical data 
and make a decision to proceed based on these results. Patients identified as not in 


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biochemical remission will not be required to have all imaging assessments described in 
Section 6.4.1 performed. 
For patients that have imaging assessments performed, the appropriate data will be sent to the 
imaging CRO for blinded independent central review to identify presence or absence of 
structural disease. Note: results from the central imaging review will not be reported to 
clinical sites. 
Briefly: 
In stage 1, suppressed Tg will be determined together with neck US assessment for all patients 
who did not require re-treatment for thyroid cancer during the first 18 months of follow up 
(refer to Section 6.4.2.1).  
In stage 2, rhTSH stimulated Tg and diagnostic WBS will be performed (refer to 
Section6.4.2.2). 
In stage 3, additional radiological imaging (chest CT and neck MRI) will be performed (refer 
to Section 6.4.2.3).   
Stage 1 assessments must be started 18 months ± 2 weeks following the patient’s RAI dose, 
and all necessary primary endpoint assessments (all 3 stages if required) must be completed 
within an 8 week period (refer also to Table 4). 
Refer to the flowchart Figure 3 for a visual representation of the staged approach for primary 
endpoint assessments. 
Refer to Section 6.4.5 for the process of determining complete remission from the primary 
endpoint assessment data. 


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Figure 3 
Flow chart for staged primary endpoint assessments 
 


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6.4.2.1 
Primary endpoint assessments Stage 1 
Patients that have been re-treated for thyroid cancer between their initial RAI dose and the 
primary endpoint assessments 18 months later (refer to Section 5.9 for re-treatment criteria), 
will not have any primary endpoint assessments performed. For the purpose of the primary 
endpoint, such re-treated patients will be determined not to be in complete remission. 
In stage 1, all patients that have not previously been re-treated for thyroid cancer will have: 

Suppressed Tg level determined by standardised central laboratory analysis.  

TSH and TgAb (using the same blood draw for suppressed Tg) determined by 
standardised central laboratory analysis. Refer to Section 6.4.3. 

Neck US assessment for structural disease to be assessed by investigator site 
review. Refer to Section 6.4.4.1. 
Suspicious lesions identified by US  5 mm in the shortest diameter should be biopsied or 
aspirated by fine needle. All biopsy/FNA samples will be assessed locally at each site. Lesions 
identified by US < 5 mm in the shortest diameter do not require a biopsy. 
All neck US and biopsy/FNA samples will be assessed locally at each site. The relevant US 
information with any biopsy findings will be provided to the imaging CRO as part of the 
blinded independent central review. 
When to proceed to stage 2 assessments 
All patients in the following situations should proceed to stage 2 assessments: 
1. 
Patients with suppressed Tg < 1 ng/mL. These patients should proceed to stage 2 
regardless of the TgAb or US results. 
2. 
Patients who are TgAb positive in stage 1 (regardless of the suppressed Tg level, 
and US results). 
3. 
Patients who fulfil either of the 2 above criteria, and have a biopsy/FNA result 
pending (ie, Investigators should not wait for the biopsy/FNA result before 
performing stage 2 assessments). 
When not to proceed to stage 2 assessments 
All patients in the following situations will be classified not in complete remission and should 
not proceed to stage 2 assessments: 
1. 
Patients who have suppressed Tg level  1 ng/mL in the absence of TgAb 
(unequivocal biochemical disease). 


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2. 
Patients with a positive biopsy/FNA that confirms the presence of structural DTC. 
Note that if the biopsy/FNA results are not yet available, the patient should not 
delay proceeding to stage 2 assessments. 
Patients who demonstrate presence of disease and do not proceed to stage 2 assessments will 
enter standard of care treatment/follow up at each centre as determined by the treating 
Investigator, and will continue to be followed in this study until 3 years following their 
initial RAI dose (refer to Section 6.4.6). 
6.4.2.2 
Primary endpoint assessments Stage 2 
In stage 2, patients will have: 

rhTSH stimulated Tg level determined by standardised central laboratory analysis.  

TgAb (from the same blood draw for rhTSH stimulated Tg) determined by 
standardised central laboratory analysis. TSH will not be analysed from this sample. 
A repeat (third) sample for TgAb analysis may be required 10 days ± 3 days later if 
the stage 1 and 2 TgAb status is discordant (refer to Table 5). 

Diagnostic nuclear medicine 131I scan (WBS) to be evaluated by blinded 
independent central review. 
These assessments will require the patient to follow a low iodine diet for a period of 1 week 
before the diagnostic 131I dose, until the diagnostic WBS assessment is completed (refer to 
Section 5.1.1 and Appendix F). Patients will also receive two Thyrogen injections (refer to 
Section 5.5.4.1) on consecutive days (day 1 and 2), followed by a diagnostic dose (5 mCi) of 
131I on either day 2 or day 3, and a blood draw for stimulated Tg central assessment and WBS 
both on day 5. 
When to proceed to stage 3 assessments 
Patients should proceed to stage 3 assessments in the absence of biochemical disease. Patients 
with stimulated Tg < 1 ng/mL and TgAb negative (for the definition of TgAb negativity refer 
to Section 6.4.3.4) should proceed to stage 3 regardless of the WBS results. 

Note that if the stage 1 and 2 blood samples are discordant for TgAb, a repeat 
(third) blood sample for central analysis is required 10 days (±3 days) later. Only if 
the third sample is negative for TgAb will the stimulated Tg level from stage 2 be 
considered to be interpretable and valid for decision making. Refer also to Table 5. 

Note also that for study purposes the WBS will evaluated by blinded independent 
central review, and even if local interpretation of WBS scan data indicates uptake 
suspicious for DTC, any biochemically negative patients must still be sent for stage 
3 assessments (in case the local and central WBS results are discordant). 


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When not to proceed to stage 3 assessments 
All patients in the following situations will be classified not in complete remission and should 
not proceed to stage 3 assessments: 
1. 
Patients who have stimulated Tg level  1 ng/mL in the absence of TgAb 
(unequivocal biochemical disease by standardised central laboratory analysis). 
2. 
Patients confirmed to be TgAb positive (regardless of all other data): 
(a) 
When both the stage 1 and 2 blood samples are TgAb positive (refer to 
Section 6.4.3.4). 
(b) 
When the repeat (third) blood sample confirms positive TgAb following a 
discordant TgAb status from stage 1 and 2.  
In these situations the stimulated Tg value will be deemed to be uninterpretable, and the 
patient will be deemed not to be in complete remission because absence of biochemical 
disease cannot be proven.  
These patients will enter standard of care treatment/follow up at each centre as determined by 
the treating Investigator, and will continue to be followed in this study until 3 years following 
their initial RAI dose (refer to Section 6.4.6). 
Note that for study purposes the WBS will evaluated by blinded independent central review. If 
local interpretation of WBS scan data indicates uptake suspicious for DTC, any biochemically 
negative patients must still be sent for stage 3 assessments (in case the local and central WBS 
results are discordant).


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Table 5 
Criteria for biochemical decision making (based on standardised central analysis results) 
Stage 1 
Stage 2 
Scenario 
Suppressed Tg 
TgAba 
Stimulated Tg 
TgAba 
Repeat 3rd TgAb 
sampleb 
Biochemical remission? 
1 
 1ng/mL 
Negative 
Not required 
Not required 
Not required 
No. Stop.c 
2 
< 1 ng/mL 
Negative 
< 1 ng/mL 
negative 
Not required 
Yes. Proceed to stage 3 
3 
< 1 ng/mL 
Negative 
 1 ng/mL 
negative 
Not required 
No. Stop.c 
4 
Any 
Positive 
< 1 ng/mL 
negative 
negative 
Yes. Proceed to stage 3 
5 
Any 
Positive 
< 1 ng/mL 
negative 
positive 
No. Stop.c 
6 
< 1 ng/mL 
Negative 
< 1 ng/mL 
positived 
negative 
Yes. Proceed to stage 3 
7 
< 1 ng/mL 
Negative 
< 1 ng/mL 
positive 
positive 
No. Stop.c 
8 
Any 
Positive 
Any 
positive 
Not required 
No. Stop.c 
a Standardised central methodology will be used to define TgAb negative/positive status, refer to Section 6.4.3.4. 
b When the TgAb results from stage 1 and 2 are discordant, a repeat (third) blood sample for TgAb is required 10 days (± 3 days) after the stage 2 blood 
sample. 
c For the purpose of the study, the patient will be deemed not to be in complete remission and no further stage 3 assessments are required. These patients will 
enter standard of care treatment/follow up at each centre as determined by the treating Investigator, and will continue to be followed in this study until 3 
years following their initial RAI dose (refer to Section 6.4.6). 
d Although this stimulated Tg blood sample is positive for TgAb, the patient will be declared to be in biochemical remission if the other two TgAb samples 
are both negative by standardised central analysis. It is not feasible to repeat a second stimulated Tg assessment.


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6.4.2.3 
Primary endpoint assessments Stage 3 
In stage 3, patients with biochemically-negative disease will have: 

Neck MRI with gadolinium contrast to be evaluated by blinded independent central 
review. 

Chest CT without contrast to be evaluated by blinded independent central review. 

If clinically indicated, a biopsy/FNA should be performed as follows: 

For any suspicious lymph nodes on MRI  15 mm in the smallest 
diameter ( 10 mm for level II, III or IV lymph nodes in the neck), or non 
nodal lesions  10 mm in the smallest diameter. 

For any chest abnormalities suspicious on CT  10 mm in the smallest 
diameter should be biopsied/FNA. 
6.4.3 
Blood sample assessments for efficacy 
All protocol-scheduled samples for serum Tg (suppressed and stimulated), TSH and TgAb 
assessment, will be sent for central laboratory analysis using standardised methodology. All 
decision making for study purposes will be based on the standardised central analysis results; 
values obtained from different assay methods may be different and cannot be used 
interchangeably.  
Full details of the sample collection, shipment and analytical methodology is provided in the 
Laboratory Manual. 
Unscheduled samples and local analysis: 
Investigators may also perform local biochemical analysis for these parameters as per standard 
site practice if desired, however this data will not be used for study-related decision making. If 
local analysis is performed, Investigators must ensure that the maximum permissible blood 
volumes for individual patients at their institutions are not exceeded.  
In the case that an investigator performs additional assessment of Tg (and TSH, TgAb) outside 
of the protocol scheduled visits, such samples should not be sent for central laboratory 
analysis. Only if such unscheduled local analysis leads the Investigator to wish to administer 
further therapy for thyroid cancer, should an additional sample ideally be sent for central 
analysis and the protocol-specified re-treatment criteria applied (Section 5.9.1.1) before the 
patient is re-treated.  
6.4.3.1 
Suppressed Tg 
Prior to the 18 month primary endpoint assessments: 
A blood sample for TSH-suppressed serum Tg is required at 9 months after the RAI dose 
(± 3 months) in order to assess whether thyroid cancer re-treatment is clinically indicated; 


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refer to the thyroid cancer re-treatment guidelines in Section 5.9.1.1. Tg assessment for this 
purpose may take place at any time from 6 months after the patient’s RAI treatment (but not 
before 6 months). A second blood sample 2-4 weeks later may also be required to verify the 
biochemical re-treatment criteria (refer to Section 5.9).  
Stage 1 primary endpoint assessments: 
For all patients that have not been re-treated for thyroid cancer prior to the primary endpoint 
assessments 18 months following their RAI dose, a blood sample to centrally analyse the 
TSH-suppressed serum Tg level will be taken. 
Anytime that a Tg blood sample is taken, the same sample will also be centrally analysed for 
TSH and TgAb (refer to Sections 6.4.3.3 and 6.4.3.4 respectively). 
The volume of blood for biochemical assessments is detailed in the Laboratory Manual for 
this study.  
6.4.3.2 
Stimulated Tg 
Prior to the 18 month primary endpoint assessments: 
Prior to the 18 month primary endpoint assessments, stimulated Tg levels are not 
recommended and not included as part of the patient follow up for this study.  
Stage 2 primary endpoint assessments: 
Serum Tg measured during TSH suppression is not sufficiently sensitive to confirm that a 
patient is free of thyroid cancer. For this reason, rhTSH (Thyrogen) stimulated serum Tg level 
will also be assessed at the primary endpoint, only for patients proceeding to stage 2 of the 
primary endpoint assessments. 
For patients that require stimulated Tg assessment, 0.9 mg of rhTSH will be administered IM 
for 2 consecutive days (refer to Section 5.5.4.1), with the blood sample taken for stimulated 
Tg central analysis on day 5. 
The volume of blood for biochemical assessments is detailed in the Laboratory Manual for 
this study.  
Each time that a blood sample is taken for central stimulated Tg analysis, the same sample 
will also be centrally analysed for TgAb (refer to Sections 6.4.3.4 respectively). 
6.4.3.3 
TSH 
Thyroid hormone supplementation will be adjusted in individual patients with the aim of 
achieving suppressed TSH levels of 0.5 mIU/L or less for the duration of the study.  Each time 
that a suppressed Tg sample is taken, TSH should also be assessed (by central standardised 
methodology). 


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The volume of blood for biochemical assessments is detailed in the Laboratory Manual for 
this study.  
6.4.3.4 
Tg antibody (TgAb)  
Each time that a blood sample is taken for central Tg analysis, the same sample will also be 
centrally analysed using standardised methodology for TgAb. Full details of the sample 
collection, shipment and analytical methodology to be used will be provided in the Laboratory 
Manual. 
TgAb cut-off for decision making 
For decision making purposes at any time in the study, standardised central analysis results 
must be used. The cut-off value for positive/negative TgAb status according to the 
standardised central methodology will be provided to sites prior to the start of recruitment. 
At screening: 
Patients with TgAbs present at screening will be ineligible for the study (refer to the exclusion 
criterion in Section 4.2, screening samples must be sent for standardised central analysis). 
Prior to the 18 month primary endpoint assessments: 
If TgAbs are detected in the follow-up Tg blood sample (at 9 months ±3 months), the patient 
should not be re-treated unless new structural disease is detected according to Section 5.9.1.2 
(ie, it is strongly recommended that patients are not re-treated on the basis of new antibodies 
alone, in the absence of structural disease). Refer to Section 5.9. 
Primary endpoint assessments (Stage 1 and 2) 
The TgAb status of the stage 1 blood sample will not be taken into consideration alone. The 
following rules will apply (refer also to Table 5): 
1. 
If both stage 1 and stage 2 blood samples are negative for TgAb, then the Tg results 
will be valid for decision making. 
2. 
If both stage 1 and stage 2 blood samples are positive for TgAb, then the stimulated 
Tg result will be deemed to be uninterpretable, and for the purpose of this study the 
patient will be classified as not in complete remission. No further primary endpoint 
assessments are required.  
3. 
If the stage 1 and 2 blood samples are discordant for TgAb status, then a repeat 
(third) blood sample is required 10 days later (± 3 days). Only if the repeat sample 
is confirmed negative for TgAb, will the stimulated Tg level in stage 2 be 
considered to be interpretable and valid for decision making.   


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6.4.4 
Imaging assessments for efficacy 
6.4.4.1 
Neck ultrasound (US) 
Neck US assessments will take place at the times indicated in the Study Plan Table 3.  Refer 
also to Section 6.4.2 and Table 4 for further details of US assessment at the primary endpoint. 
Any suspicious lymph nodes or lesions in the neck  5 mm in the smallest diameter identified 
by US during the study should be biopsied/FNA. 
Note: for a lesion to be suspicious it must be new or enlarged compared to the previously 
obtained imaging data, and be consistent with the biological characteristics of DTC. 
Biopsy/FNA samples, where performed, will be assessed at each site. Needle washout may be 
analysed locally for Tg according to local standard practice. The totality of the information 
obtained from a biopsy/FNA (including washout Tg data where analysed), will be assessed 
locally to determine presence or absence of thyroid cancer in the sample. 
US definition of structural DTC 
Any soft tissue or lymph node lesions that are new or enlarged compared to previous 
ultrasound assessment (either post operatively and/or at 9 months) that are consistent with the 
biological characteristics of DTC and fulfil the following criteria will be considered as 
structural thyroid cancer: 

Lesions of any size confirmed to be structural DTC by positive biopsy/FNA (ie, 
biopsy proven). 

Any suspicious lesion or lymph node of any size that is subsequently shown to be 
RAI avid/positive on central review of WBS (in this situation the positive WBS 
data takes precedent over a negative biopsy/FNA from the same lesion/lymph node 
if performed).  
Note, any abnormality on US that is non-RAI avid on the subsequent WBS, will be considered 
benign even in the absence of a biopsy. 
The assessment of neck US and biopsy/FNA sample will be made by investigator site review. 
The local ultrasound information will be recorded in the eCRF (with FNA/biopsy results if 
performed) and provided to the central imaging CRO if necessary as supporting clinical data 
(refer to Section 6.4.4.6).     
Guidelines for standardised acquisition, defining suspicious lesions and reporting of US 
assessments required for this study will be provided to each study site. 


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6.4.4.2 
Whole body diagnostic 131I nuclear medicine scan (WBS) 
Pre-RAI treatment 
There is no pre-ablation WBS in this study. This is a fixed RAI dose study (100mCi, 3.7GBq) 
with Thyrogen stimulation. Study-specific post-operative imaging will be used to ensure that 
enrolled patients do not have overt macronodular disease remaining in the neck or distant 
metastatic disease in the lungs.  
Post-RAI treatment 
All randomised patients will have a WBS performed 3-10 days following their RAI treatment 
dose to assess where the administered 131I has localised. 
It is acknowledged that this assessment may identify a small number of patients with distant 
metastatic disease that was not previously identified (patients with known metastatic disease 
at study entry will be excluded). Such patients will continue in the study and should not be 
withdrawn; they will continue to be followed according to the protocol and will be included in 
both the Intention To Treat (ITT) efficacy and safety analysis sets for the study. 
Primary endpoint (stage 2) 
If required according to Section 6.4.2, the diagnostic WBS to assess the primary endpoint will 
be performed following a diagnostic dose of 5 mCi 131I (refer to Section 5.5.4.2). Patients will 
receive 2 Thyrogen injections on consecutive days (day 1 and 2), followed by a diagnostic 
dose (5 mCi) of 131I on either day 2 or day 3, and a blood draw for stimulated Tg central 
assessment and WBS both on day 5. Patients will be required to adhere to a low iodine diet for 
a period of 1 week before the diagnostic 131I dose, until the diagnostic WBS assessment is 
completed. 
Standardised acquisition and submission guidelines for every WBS procedure will be 
provided separately to this protocol. 
WBS definition of structural DTC 
The WBS evaluation will be made by blinded, independent central review. 
If the central review determines no visible 131I uptake then the WBS for that patient will be 
considered normal/negative (no disease).  Areas considered to be anatomically normal (for 
example uptake in the salivary glands, stomach, gastrointestinal, urinary tract and bladder) 
will not be considered disease. 
If the central review determines there is a low level of visible uptake in the thyroid bed: 

Uptake must be < 0.1% to be considered normal/negative (no disease). 

If uptake in the thyroid bed region is  0.1%, the patient will be deemed not to be in 
remission due to the presence of iodine-avid DTC. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
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The % uptake in the thyroid bed (using the region-of-interest method drawn over the thyroid 
bed) will be measured and calculated by the local Investigator site and entered into the eCRF, 
to be made available to the central reviewer. 
If an abnormality identified by US  is subsequently shown to be RAI avid on WBS, the WBS 
data takes precedent over a negative biopsy/FNA. 
6.4.4.3 
Neck MRI 
Post-operative (screening) 
This baseline assessment is performed to determine study eligibility according to Section 4.1).  
The baseline post-operative images will be available at the central imaging CRO to aid 
interpretation of the primary endpoint image central read if necessary (refer to Section 6.3). 
Primary endpoint (stage 3) 
Neck MRI to define the primary endpoint will be performed in stage 3 of the assessments in 
patients deemed to be biochemically-negative for thyroid cancer. Refer to Section 6.4.2.3 and 
Figure 3. 
The neck MRI must be performed using T1 weighted image sequences with and without 
gadolinium contrast agent, and T2 weighted image sequences. 
If clinically indicated, any suspicious lymph nodes on MRI  15 mm in the smallest diameter 
( 10 mm for level II, III or IV lymph nodes in the neck), or non nodal lesions  10 mm in the 
smallest diameter, should be biopsied/aspirated by fine needle.  
MRI definition of structural DTC 
New lesions (nodal or non-nodal) or significantly enlarged lymph node lesions compared to 
previous post operative (screening) MRI which are consistent with the biological 
characteristics of DTC and fulfil either of the following criteria will be considered to represent 
structural thyroid cancer: 

Lesions of any size confirmed to be structural DTC by positive biopsy/FNA (ie, 
biopsy proven). 

Any suspicious lesion or lymph node of any size that is shown to be RAI 
avid/positive on WBS (in this situation the positive WBS data takes precedent over 
a negative biopsy/FNA from the same lesion/lymph node if performed).  
Note, any abnormality on MRI that is non-RAI avid on the WBS, will be considered benign 
even in the absence of a biopsy. 
This assessment will be made by blinded, independent central review. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
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Edition Number 3 
Date 15 July 2013 
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6.4.4.4 
Chest CT 
In this study all chest CT procedures should be performed without iodine containing contrast 
agent. 
Post-operative (screening) 
This baseline assessment is performed to determine study eligibility according to Section 4.1).  
The baseline post-operative images will be available at the central imaging CRO to aid 
interpretation of the primary endpoint image central read if necessary (refer to Section 6.3). 
Primary endpoint (stage 3) 
Chest CT to define the primary endpoint will be performed in stage 3 of the assessments in 
patients deemed to be biochemically-negative for thyroid cancer. Refer to Section 6.4.2.3 and 
Figure 3. 
If clinically indicated, any chest abnormalities suspicious on CT  10 mm in the smallest 
diameter should be biopsied/FNA. 
CT definition of structural DTC 
New lesions (nodal or non-nodal) or significantly enlarged lymph node lesions compared to 
previous post operative (screening) CT which are consistent with the biological characteristics 
of DTC and fulfil either of the following criteria will be considered to represent structural 
thyroid cancer: 

Lesions of any size confirmed to be structural DTC by positive biopsy/FNA (ie, 
biopsy proven). 

Any suspicious lesion or lymph node of any size that is shown to be RAI 
avid/positive on WBS (in this situation the positive WBS data takes precedent over 
a negative biopsy/FNA from the same lesion/lymph node if performed).  
Note, any abnormality on CT that is non-RAI avid on the WBS, will be considered benign 
even in the absence of a biopsy. 
This assessment will be made by blinded, independent central review  
6.4.4.5 
Biopsy or fine needle aspirate (FNA) 
A biopsy or FNA should be performed in the following situations: 

US: For any suspicious lymph nodes or lesions in the neck  5 mm in the smallest 
diameter identified by US during the study. 

MRI: If clinically indicated, for lymph nodes suspicious on MRI  15 mm in the 
smallest diameter ( 10 mm for level II, III or IV lymph nodes in the neck), or non 
nodal lesions  10 mm in the smallest diameter. 


Clinical Study Protocol 
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Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
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
CT: If clinically indicated, for any chest abnormalities suspicious on CT  10 mm 
in the smallest diameter. 
Note: for a lesion to be suspicious it must be new or enlarged compared to the previously 
obtained imaging data, and be consistent with the biological characteristics of DTC. 
All biopsy/FNA samples taken during the study will be assessed at each site according to local 
standard practice. Needle washout may be analysed locally for Tg according to local standard 
practice (this is not a mandatory requirement). The totality of the information obtained from a 
biopsy/FNA (including washout Tg data where analysed), will be assessed locally to 
determine presence or absence of thyroid cancer in the sample. This information will be 
provided to the central imaging CRO. 
Refer to Section 6.10.3 for details regarding tumour sample acquisition on disease 
progression. 
6.4.4.6 
Information to be sent to the central imaging CRO 
The following information will be sent to the central imaging CRO (further details are 
provided in the imaging charter/guidelines for this study). 
1. 
Post-operative screening assessments (refer to Section 6.3): images for chest CT 
and neck MRI. This data must be sent for all patients as soon as possible after each 
patient is randomised.  
2. 
Post-RAI WBS images taken 3-10 days after each patient’s RAI dose. This data 
must be sent for all patients as soon as possible after each patient has their post-RAI 
WBS assessment. 
3. 
Primary endpoints assessments stage 1: site ultrasound and biopsy information. The 
required data must be entered into the clinical database for each patient as soon as 
possible after completion of the assessment (NOTE: this information is not sent to 
the central imaging CRO, but instead must be entered into the database directly 
using eCRF). 
4. 
Primary endpoint assessments stage 2: diagnostic WBS images. This data must be 
sent for all patients as soon as possible after completion of the assessment. 
5. 
Primary endpoint assessments stage 3: chest CT and neck MRI images and biopsy 
information (if performed). This data must be sent for all patients as soon as 
possible after completion of the assessments. Biopsy data must be entered into the 
clinical database for each patient as soon as possible after completion of the 
assessment. 


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Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
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6.4.5 
Derivation of primary endpoint of complete remission 
The complete remission status of each patient will be determined programmatically by 
AstraZeneca, by incorporating data on re-treatment provided by the site, biochemical data 
from the standardised central laboratory analysis, and structural disease assessment from the 
blinded, independent central review.  
If a patient has received further therapy for thyroid cancer prior to the primary endpoint 
assessment, the patient will be classified as not in complete remission and no further data will 
be considered. 
For patients that have not received further therapy for thyroid cancer, all available imaging 
data will be sent to the imaging CRO.  Determination of presence or absence of structural 
thyroid cancer will be made by the imaging CRO only for biochemically negative patients. A 
list of biochemically negative patients (based on standardised central laboratory analysis) will 
be provided by AstraZeneca to the imaging CRO to enable them to identify which patients to 
assess. 
The imaging CRO will assess the WBS, MRI and CT and also review the site assessment of 
neck US to provide an overall assessment: presence or absence of structural thyroid cancer, or 
not evaluable based on all of the available information. For the derivation of the complete 
remission endpoint, patients that are not evaluable for structural disease assessment will be 
considered as not achieving complete remission, regardless of the result of other assessments.    
AstraZeneca will programmatically combine information on further therapy, biochemical data, 
and the determination of structural disease from the central imaging CRO, to determine the 
complete remission status of each patient as shown in Table 6. 
The dates on which assessments were performed will be incorporated into the derivation of 
the primary endpoint to ensure patients are assessed within a time window around the 
scheduled 18 month post-RAI treatment. The first assessment must be started at 18 months 
± 2 weeks following the patient’s RAI dose, and all necessary primary endpoint assessments 
must be completed within a 8 week period. If a patient has assessments/scans that fall outside 
of these time windows, the patient will be considered not to be in complete remission, 
regardless of the assessment of disease status. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
83(118) 
Table 6 
Programmatic derivation of complete remission status 
Biochemical datab 
Scenario 
Further 
thyroid cancer 
therapya       
(re-treatment) 
Stimulated Tgb 
TgAbb 
Structural 
disease 
assessmentc 
Complete 
remission 
1 
Yes 
N/A 
N/A 
N/A 
No 
2 
No 
< 1 ng/mL 
Negatived 
Absence of 
disease 
Yes 
3 
No 
 1ng/mL 
Any 
Any 
No 
4 
No 
Any 
Positived 
Any 
No 
5 
No 
Any 
Any 
Presence of 
disease 
No 
6 
No 
NE 
Any 
Any 
No 
7 
No 
Any 
NE 
Any 
No 
8 
No 
Any 
Any 
NE 
No 
a As assessed by investigator at site. 
b As assessed by standardised central laboratory analysis. 
c As assessed by blinded, independent central review. 
d  If the stage 1 and 2 blood samples are discordant for TgAb status, then a third blood sample 10 days later (± 3 days) is required. Only if the third sample is 
negative for TgAb will the overall TgAb result be considered negative for the primary endpoint assessments. Refer also to Table 5. 
N/A primary endpoint assessments are not required for patients that have received further treatment for thyroid cancer in the previous 18 months. 
NE Not evaluable (for example due to missing samples or assessments). 
 


Clinical Study Protocol 
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Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
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6.4.6 
Clinical remission 
The secondary efficacy endpoint for this study is clinical remission rate at 18 months 
(following RAI treatment). This is designed to more typically reflect clinical practice. As 
such, the definition of clinical remission will exclude the additional radiological assessments 
performed for the purpose of complete remission in this study. 
Definition of clinical remission: 
Patients will be defined to be in clinical remission if all of the following criteria can be 
demonstrated: 
1. 
Serum Tg levels < 1ng/mL during rhTSH stimulation, in the absence of interfering 
Tg antibodies, as assessed by standardised central laboratory analysis. 
2. 
No confirmed evidence of thyroid cancer on neck US, as assessed by investigator 
site review. 
3. 
No evidence of thyroid cancer on diagnostic WBS, as assessed by blinded 
independent central review.  
4. 
No histopathological evidence of thyroid cancer on FNA/biopsy when performed to 
clarify equivocal US findings, as assessed by investigator site review. 
5. 
No further thyroid cancer therapy was administered in the first 18 months following 
the initial RAI treatment.  
6.4.7 
Derivation of clinical remission status 
The clinical remission status of each patient will be determined programmatically by 
AstraZeneca, by incorporating data on re-treatment provided by the site, biochemical data 
from the standardised central laboratory analysis, structural disease assessment based on US 
by investigator site review and structural disease assessment based on WBS from the blinded, 
independent central review.  
If a patient has received further therapy for thyroid cancer prior to the primary endpoint 
assessment, the patient will be classified as not in clinical remission and no further data will 
be considered. 
For patients that have not received further therapy for thyroid cancer: 
A determination of presence or absence of structural thyroid cancer or not evaluable will be 
made by the investigator based on US.  
A determination of presence or absence of structural thyroid cancer or not evaluable will be 
made by the central imaging CRO based on WBS for only biochemically negative patients. 
Information on US will not be reviewed as part of this assessment. A list of biochemically 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 3 
Date 15 July 2013 
85(118) 
negative patients (based on standardised central laboratory analysis) will be provided by 
AstraZeneca to the imaging CRO to enable them to identify which patients to assess. 
AstraZeneca will programmatically combine information on further therapy, biochemical data, 
determination of structural disease from the investigator site assessment of US and 
determination of structural disease from the central imaging CRO of WBS, to determine the 
clinical remission status of each patient.  
Full details of the programmatic derivation of clinical remission will be provided in the SAP. 
6.4.8 
Final study follow up at 3 years 
The final study follow-up will take place 3 years post-RAI for each patient, and will include: 
1. 
The clinical status of each patient, for example: remission, persistent disease, 
recurrent disease, survival status. 
2. 
The incidence of further therapy (re-treatment) for thyroid cancer, for example, 
additional RAI or surgery. 
3. 
Final assessment of selumetinib or RAI-related AEs and SAEs. 
Note, following the primary endpoint assessments until the final study visit at 3 years 
following each patient’s initial RAI treatment, each patient will enter standard of care 
treatment or follow up according to local practice. No study-specific assessments will be 
performed, and locally performed assessments and data will not typically be collected as 
routine in the clinical study database (except for safety data, refer to Section 6.5.3). The 
patient’s clinical status at the final study follow up will be collected (along with any relevant 
supporting local assessment data). For example, remission status will be defined by the 
Investigator on the eCRF based on the relevant local standard of care assessments (eg, locally 
assessed Tg and no evidence of thyroid cancer on locally assessed US). 
6.5 
Safety 
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. 
6.5.1 
Definition of adverse events  
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition 
can be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the 
abnormal results of an investigation (eg, laboratory findings, electrocardiogram).  In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered. 
The term AE is used to include both serious and non-serious AEs. 


Clinical Study Protocol 
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6.5.2 
Definitions of serious adverse event 
A serious adverse event is an AE occurring during any study phase (ie, run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria: 

Results in death 

Is immediately life-threatening 

Requires in-patient hospitalisation or prolongation of existing hospitalisation  

Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions 

Is a congenital abnormality or birth defect 

Is an important medical event that may jeopardise the patient or may require 
medical intervention to prevent one of the outcomes listed above 
For further guidance on the definition of a SAE, see Appendix B to the Clinical Study 
Protocol. 
6.5.3 
Recording of adverse events 
All adverse events will be graded according to NCI CTCAE Version 4. 
Time period for collection of adverse events 
All AEs/SAEs will be collected from informed consent until 30 days following the last dose of 
study treatment (selumetinib or placebo).  
After this time: 

all SAEs regardless of causality will be collected until the final study 
follow-up (3 years post-RAI for each patient, refer to Section 6.4.8) 

only AEs considered causal to RAI or the combination of RAI and study 
treatment will be collected until the final study follow-up (3 years post-
RAI for each patient, refer to Section 6.4.8). 
Follow-up of unresolved adverse events 
Any AE or laboratory change occurring during the study treatment period should be followed 
up by the investigator for as long as medically indicated (resolution or stabilisation), and 
follow up information  recorded in the eCRF. 
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the CRF. 


Clinical Study Protocol 
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Edition Number 3 
Date 15 July 2013 
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AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
Variables 
The following variables will be collected for each AE: 

AE (verbatim) 

The date when the AE started and stopped 

CTCAE grade information 

Whether the AE is serious or not 

Investigator causality rating against the Investigational Product (yes or no) and/or 
RAI (yes or no) 

Action taken with regard to investigational product 

AE caused patient’s withdrawal from study treatment 

Treatments patient received for AE 

Outcome 

Whether event constitutes an SAE. 
In addition, the following variables will be collected for SAEs: 

Date AE met criteria for serious AE 

Date Investigator became aware of serious AE 

AE is serious due to 

Date of hospitalisation 

Date of discharge 

Probable cause of death (if applicable) 

Date of death (if applicable) 

Autopsy performed (if applicable) 
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.5.2.  An AE of severe 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
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Edition Number 3 
Date 15 July 2013 
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intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE. On the other hand, a stroke 
that results in only a limited degree of disability may be considered a mild stroke but would be 
a SAE. 
Causality collection 
The Investigator will assess causal relationship between Investigational Product and RAI and 
each Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’ 
For SAEs causal relationship will also be assessed for other medication, study procedures and 
additional study drug (eg, RAI).  Note that for SAEs that could be associated with any study 
procedure the causal relationship is implied as ‘yes.’ 
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol. 
Adverse Events based on signs and symptoms 
All AEs spontaneously reported by the patient, or reported in response to the open question 
from the study personnel: ‘Have you had any health problems since the previous visit/you 
were last asked?’ or revealed by observation, will be collected and recorded in the CRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately. 
Adverse Events based on examinations and tests 
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
clinical study report.  Deterioration as compared to baseline in protocol-mandated laboratory 
values, vital signs etc should therefore only be reported as AEs if they fulfil any of the SAE 
criteria or are the reason for discontinuation of treatment with the investigational product. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s). 
After the 30 day follow up visit, AEs associated with RAI or the combination of study 
treatment and RAI, should continue to be collected by AE reporting, these would include 
abnormalities, for example, white blood cell count or Hb reductions.  
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 


Clinical Study Protocol 
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Edition Number 3 
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Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
Cases where a patient shows an AST or ALT 3xULN or total bilirubin  2xULN may need 
to be reported as SAEs, please refer to Appendix D ‘Actions required in cases of combined 
increase of aminotransferase and total bilirubin – Hy’s Law,’ for further instructions. All 
patients with an AST, ALT or bilirubin value above ULN at time of the last dose of 
selumetinib/placebo should have a further liver chemistry profile (AST, ALT, bilirubin and 
ALP) performed 30 days (± 7 days) later for follow-up. 
6.5.3.1 
Disease progression 
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the investigational product is being studied.  It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease.  Events, 
which are unequivocally due to disease progression, should not be reported as an AE during 
the study. 
6.5.4 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the CRF. 
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
appropriate AstraZeneca representatives immediately, or no later than 24 hours of when he 
or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within one 
calendar day of initial receipt for fatal and life threatening events and within five calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative. 
If the WBDC system is not available, then the Investigator or other study site personnel 
reports a SAE to the appropriate AstraZeneca representative by telephone. 
The AstraZeneca representative will advise the Investigator/study site personnel how to 
proceed. 


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Edition Number 3 
Date 15 July 2013 
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The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug. 
6.5.5 
Laboratory safety assessment 
Blood and urine samples for determination of clinical chemistry, haematology and urinalysis 
will be taken at the times indicated in the Study Plan (Table 3). For samples taken after Day 1 
during the study treatment period, the sample may be taken any time of day (ie, it does not 
matter whether it is pre-dose or post-dose). Day 1 samples should be taken pre-dose. 
The following laboratory variables will be measured: 
Table 7 
Laboratory safety assessments 
Clinical chemistry 
Haematology 
Urinalysis a 
s-Albumin 
Erythrocyte count 
u-Albumin 
s-ALT 
Haemoglobin 
u-Creatinine 
s-AST 
Platelet count 
 
s-ALP 
Leucocyte cell count 
 
s-Total Calcium 
Leucocyte differential count (absolute count): 
 
s-Creatinine 
Neutrophils 
 
s-Gamma glutamyl transferase (GT) 
Eosinophils 
 
s-Glucose 
Basophils 
 
s-Magnesium 
Lymphocytes 
 
s-Phosphate 
Monocytes 
 
s-Potassium 
 
 
s-Sodium 
 
 
s-Total protein 
 
 
s-Total bilirubin 
 
 
s-Urea nitrogen 
 
 
s-Creatine kinase 
 
 
a A single-spot urine specimen will be collected on the day of scheduled visit, at sites where the local laboratory 
is able to determine the concentration of urine albumin and urine creatinine from a single-spot urine specimen.  
Investigational sites unable to report these parameters will perform routine urinalysis according to the local 
standard of care.  
s serum 
u urine  
 
All laboratory safety assessments will be analysed by the local laboratory. 
Clinical chemistry, haematology and urinalysis testing will be repeated as clinically indicated 
as part of the routine management of the patient on the occurrence of AEs. 
For blood volume see Table 9. 


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6.5.6 
Physical examination 
A complete physical examination will be performed at the times indicated in the Study Plan 
Table 3. 
6.5.7 
Cardiac monitoring 
Note: troponin assessment in this study is only required for cardiac AE follow up as clinically 
indicated. 
6.5.7.1 
ECHO or MUGA 
An ECHO or MUGA assessment (according to site preference) will be conducted at the 
timepoints indicated in the Study Plan (Table 3). A further assessment should be performed as 
part of the assessment package for any cardiorespiratory adverse event with no obvious 
diagnosis.  Medical management of the event should follow local clinical practice.  
Selumetinib interruption should be considered until resolution of the event or until return to 
baseline. 
LVEF can be measured in many different ways but echography is the preferred choice when 
possible.  The same modality should be used as baseline for any ECHO/MUGA follow up. 
Recommendations include  having complete high quality standardized 2-D with Doppler 
echocardiographic examinations performed by an experienced sonographer (preferably with 
the same operator performing all studies for a given patient), according to a specified protocol 
including evaluation of both systolic and diastolic left ventricular function.  Ejection fraction 
determinations should be assessed quantitatively based on bi-plane measurements of end 
diastolic and end systolic left ventricular volumes. 
6.5.7.2 
Resting 12-lead ECG 
ECGs will be analysed locally at each site.  Patients should be supine and at rest 10 minutes 
prior to recording the ECG. 
Parameters including heart rate, duration of QRS complex, PR and QT intervals will be 
collected.  R-R interval and QTcF will be calculated by AstraZeneca from the data provided. 
The investigator should review the paper copy of the ECGs on each study day and may refer 
to a local cardiologist if appropriate. 
Any symptoms from the patient should be registered as a comment and if AE criteria are met, 
recorded as an AE. 
At screening all patients will have a single 12-lead ECG performed.  The screening ECG can 
be conducted up to 28 days prior to randomisation. 
During the treatment phase of the study, patients will have single 12-lead ECGs assessments 
at the following timepoints: 

1-2 hours after the first dose of study treatment on Day 1 


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
1-2 hours after the morning dose of study treatment on Day 29 or 30 

At the 30-day follow up visit following completion of study treatment   

Single ECGs must also be performed at the time of any ECHO/MUGA assessment, 
and on occurrence of any cardiorespiratory adverse event   

A single 12-lead ECG is also required at premature discontinuation of treatment 
6.5.8 
Vital signs 
Resting blood pressure and pulse rate will be measured using a semi-automatic blood pressure 
recording device with an appropriate cuff size.  Vital sign assessments, including weight, will 
be performed at the times indicated in the Study Plan Table 3. Pulse and blood pressure must 
also be performed at the time of any ECHO/MUGA assessment, and on occurrence of any 
cardiorespiratory adverse event.  Height will be assessed at Visit 1 only.   
Any changes in vital signs should be recorded as an AE if applicable. 
6.5.9 
Other safety assessments 
6.5.9.1 
Pregnancy test 
A serum or urine pregnancy test (according to local practice) will be performed at the times 
indicated in the Study Plan Table 3. Following the RAI treatment, monitoring for pregnancy 
will be performed according to standard clinical practice at each centre. 
6.5.9.2 
Ophthalmologic examination 
An ophthalmologic examination (best corrected visual acuity, intraocular pressure, slit lamp 
fundoscopy) should be performed at the timepoints indicated in the Study Plan (Table 3), and 
if a patient experiences a visual symptoms (including blurring of vision) with additional tests 
if clinically indicated e.g. consider OCT scans. 
Patients who have a retinal abnormality prior to discontinuation of selumetinib/placebo should 
have a follow up eye examination performed within 30 days after discontinuation of 
selumetinib/placebo in order to document reversibility. 
An algorithm for management and investigation of visual symptoms is provided in 
Appendix G: “Guidance for Management of Adverse Events in Studies of Selumetinib.” 
6.6 
Patient reported outcomes (PRO) – not applicable 
Patient reported outcomes will not be collected in this study. 


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6.7 
Pharmacokinetics  
6.7.1 
PK samples required 
Blood samples (2 mL) for determination of plasma concentrations of selumetinib and 
N-desmethyl selumetinib will be collected from every patient according to the time points 
below.  Other metabolites (eg, selumetinib amide) may also be determined in the PK analysis. 
Each patient will be asked to contribute 8 blood samples, one from each of the pre defined 
time windows below on both Day 1 and Day 29 or Day 30.  The Day 29 or Day 30 PK blood 
samples may be taken earlier, from Day 22 onwards of study treatment if preferred, but it is 
essential that all PK blood samples are collected on a visit day prior to the RAI dose being 
administered.  

Pre-dose (within 15 minutes of dosing) 

Between 15 minutes and 1 hour post-dose 

Between 1.5 and 2.5 hours post-dose 

Between 3 and 8 hours post-dose 
Depending on emerging data/information, the timings and number of the PK samples may be 
altered, but the maximum total blood volumes given in Table 9 will not be exceeded.  The 
actual sample date and time of all PK samples must be recorded in the eCRF. 
Samples will be collected, labelled, stored and shipped as detailed in Laboratory Manual.  
6.7.2 
Determination of drug concentration 
Samples for determination of selumetinib and N-desmethyl selumetinib concentrations in 
plasma will be analysed by Covance on behalf of Clinical Bioanalysis Alliance, AstraZeneca 
R&D, using an appropriate bioanalytical method. Other metabolites (eg, selumetinib amide) 
may also be determined in the PK analysis. Full details of the bioanalytical method used will 
be described in a separate bioanalytical report. 
For each placebo patient, samples will only be analysed on a ‘for cause’ basis, for example, if 
no quantifiable concentrations were observed in a patient’s samples when the drug was 
expected to be present. 
All samples still within the known stability of the analytes of interest (ie, selumetinib, N-
desmethyl selumetinib and its metabolites) at the time of receipt by the bioanalytical 
laboratory will be analysed. 
6.8 
Pharmacodynamics – not applicable 
Pharmacodynamic samples will not be taken during this study.  


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6.9 
Pharmacogenetics 
6.9.1 
Genetic blood sample at study entry 
An optional blood sample for genetic research will be obtained from eligible patients at Visit 1 
or 2 ideally.  If for any reason the sample is not drawn at Visit 1 or 2, it may be taken at any 
visit before the RAI dose is administered (radioactive samples for this purpose will not be 
accepted).  Although genotype is a stable parameter, early sample collection is preferred to 
avoid introducing bias through excluding patients who may withdraw due to an adverse event 
(AE), such patients would be important to include in any genetic analysis.  Only one sample 
should be collected per patient for this purpose.  Samples will be collected, labelled, stored 
and shipped as detailed in the Laboratory Manual. 
For blood volumes see Section 7.1. 
6.10 
Biomarker analysis 
6.10.1 
BRAF and NRAS patient population 
Archival tumour sample from each patient will be analysed for BRAF and NRAS mutational 
status centrally using standardised methodology. Analysis may include, but is not limited to, 
BRAF V600E and NRAS Q61R, Q61K, Q61L.Full analytical methodology details will be 
provided in the CSR. 
The genetic analysis of archival tumour samples to identify the BRAF and NRAS patient 
population will be performed retrospectively in the study (after randomisation but prior to the 
primary endpoint data analysis). 
BRAF/NRAS positive = mutations in BRAF/NRAS have been detected 
BRAF/NRAS not detected = no mutation in BRAF/NRAS has been detected   
BRAF/NRAS unknown = mutation status in BRAF/NRAS cannot be confirmed 
6.10.1.1 Archival tumour sample 
All patients will be required to provide consent for AstraZeneca to collect and analyse 
samples of their previously obtained tumour material (ie, from their recent surgery) for 
analysis of biomarkers relevant to DTC. Archival tumour sample provision is mandatory in 
this study, and each Investigator should make every effort to collect a sample from all 
randomised patients.  It is accepted that it may not be possible to obtain all samples prior to 
commencement of study treatment (which should continue as planned).  However, it should be 
established during the screening period that sufficient sample exists and is available. Samples 
are expected to be made available as soon as possible. Note, no replacements will be made for 
patients where an archival tumour sample is not provided. 
These samples will be analysed for the biomarkers necessary for the definition of the second 
primary objective patient population (BRAF and NRAS mutational status), and may also be 


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used for exploratory analyses on residual material. Such analyses may include (but are not 
restricted to): 

Mutational status of BRAF and NRAS genes, RET rearrangements, and other known 
MAPK and PI3K effector oncogenes.  

Baseline expression of pathway and thyroid differentiation specific genes such as 
NIS, Tg, TPO, and PAX8. 

Comprehensive genetic analysis to ensure coverage of the major mutational events 
in DTC. 
The exploratory analyses from tumour material may include but are not limited to mRNA 
expression profiling, microRNA expression profiling, gene copy number analysis and protein 
expression by immunohistochemistry for any markers relevant to DTC, either known at the 
time of analysis, or identified in the future. 
For the tumour samples detailed below, each site will be asked to provide one of the following 
for each randomised patient: 

Formalin-fixed, paraffin-embedded tumour tissue block, 
or 

20 pre-cut sections from formalin-fixed paraffin-embedded tumour tissue 
block, presented on slides. Each section is to be 5 m thick.  
Sites should ship the tumour sample as soon as it is available.  If mutational status cannot be 
adequately determined from the initial tumour biopsy sample, and histopathological review 
shows it to be a poor quality sample, a second sample should be submitted for re-testing.   
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual. 
If requested, unused tumour samples will be repatriated.  For further details see the Laboratory 
Manual. 
6.10.2 
Collection of plasma and serum for exploratory biomarker research 
All randomised patients will be required to provide a blood sample at or before randomisation, 
and disease progression (for example, when the patient is re-treated for persistent or recurrent 
thyroid cancer) for exploratory biomarker research. 
All patients will be required to provide: 

1x 10ml blood sample for preparation of serum at randomisation (any 
time before the first dose of study treatment for eligible patients) and 
disease progression. 


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1x 10ml blood sample for preparation of plasma at randomisation (any 
time before the first dose of study treatment for eligible patients) and 
disease progression. 
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual. 
Residual material may be used for exploratory biomarker research. 
6.10.3 
Collection of disease progression tumour sample 
Patients will be asked to provide a tumour sample removed during the study when the patient's 
cancer is deemed to have progressed (for example, when the patient is re-treated for persistent 
or recurrent thyroid cancer, or has had further surgery). This is an optional sample. 
This will enable a comparison to be made of (for example) tumour genetics and relevant 
signal transduction pathways between the randomisation and the disease progression tumour 
sample and also the evolution of the tumour biology in response to treatment with selumetinib 
can be explored. Such changes may reflect an evolution in phenotype of the tumour, which 
ultimately may guide future treatment decisions post progression on selumetinib. 
Samples can be of any type (such as FNA, or tumour sample taken from a surgical procedure 
performed as part of the patient’s disease management plan), and will be collected, labelled, 
stored and shipped as detailed in the Laboratory Manual. 


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Table 8 
Biomarker summary table 
Biomarker sample 
Time point 
Protocol Section 
Archival tumour for NRAS and BRAF 
analysisa 
Randomisation 
6.10.1.1 
Plasma sample for exploratory biomarker 
analysis 
Randomisation and disease 
progression 
6.10.2 
Serum sample for exploratory biomarker 
analysis 
Randomisation and disease 
progression 
6.10.2 
Disease progression tumour biopsy 
(optional) 
Disease progression 
6.10.3 
Blood sample for genetic analysis 
(optional) 
Randomisation 
6.9.1 
a Residual tissue sample material will be stored for potential retrospective biomarker analysis, which will be 
performed in an AstraZeneca laboratory or AstraZeneca approved laboratory. 
7. 
BIOLOGICAL SAMPLING PROCEDURES  
7.1 
Volume of blood 
The total volume of blood (maximum) that will be drawn from each patient in this study is as 
follows: 
Table 9 
Volume of blood to be drawn from each patient  
Assessment 
Maximum 
sample 
volume a 
(mL) 
Typical 
number of 
samples (over 
18+ months) 
Total volume 
(mL) 
Safety 
Clinical chemistry (local analysis) 
5 
5 
25 
 
Haematology (local analysis) 
3 
7 
21 
Efficacy 
Tg, TSH, TgAb (central analysis) 
10 
4b 
40 
PK 
2 
8 
16 
Genetics at randomisation (optional) 
10 
1 
10 
Exploratory biomarkers at randomisation, serum  
10 
1 
10 
Exploratory biomarkers at randomisation, plasma  
10 
1 
10 
Exploratory biomarkers on progression, serum  
10 
1 
10 
Exploratory biomarkers on progression, plasma  
10 
1 
10 
Total 
 
 
152 b 
a All volumes presented are maximums. The actual volume requirements will be detailed in the Laboratory Manual. 
b For efficacy samples up to 2 repeat samples may be required, this would result in 10-20 mL additional blood and bring the maximum total 
to 172 mL. 


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7.2 
Handling, storage and destruction of biological samples 
Biological samples for future research may be retained at or on behalf of AstraZeneca for a 
maximum of 25 years following the Last Patient’s Last Visit in the study.  The results from 
future analysis will not be reported in the Clinical Study Report but separately in a Scientific 
Report or Scientific Publication. 
7.2.1 
Pharmacokinetic samples 
Samples will be anonymised by pooling or will be disposed of after the Bioanalytical report 
finalisation or six months after issuance of the draft Bioanalytical report (whichever is earlier), 
unless requested for future analyses. Pooled, anonymised samples may be used for analytical 
method development and/or validation. Anonymised samples will be retained for no more 
than 5 years after the CSR is finalised. Samples may also be disposed of earlier, pending 
further notification. 
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation will not be reported in the Clinical Study 
Report but separately in a Bioanalytical report. 
7.2.2 
Pharmacogenetic samples 
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality.  Samples will be stored for a maximum of 25 
years, from the date of the Last Patient’s Last Visit, after which they will be destroyed.  DNA 
is a finite resource that may be used up during analyses.  Samples will be stored and used until 
no further analyses are possible or the maximum storage time has been reached. 
For all samples irrespective of the type of coding used the DNA will be extracted from the 
blood sample.  The DNA sample will be assigned a unique number replacing the information 
on the sample tube. Thereafter, the DNA sample will be identifiable by the unique DNA 
number only.  The DNA number is used to identify the sample and corresponding data at the 
AstraZeneca genetics laboratories, or at the designated contract laboratory.  No personal 
details identifying the individual will be available to any person (AstraZeneca employee or 
contract laboratory staff working with the DNA.) 
The samples and data for genetic analysis in this study will be single coded.  The link between 
the patient enrolment/randomisation code and the DNA number will be maintained and stored 
in a secure environment, with restricted access WITHIN the Clinical Genotyping Group 
Laboratory Information Management System (LIMS) at AstraZeneca.  The link will be used 
to identify the relevant DNA samples for analysis, facilitate correlation of genotypic results 
with clinical data, allow regulatory audit and to trace samples for destruction in the case of 
withdrawal of consent when the patient has requested disposal/destruction of collected 
samples not yet analysed.  


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7.3 
Labelling and shipment of biohazard samples 
The Principal Investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria), 
see Appendix C ‘IATA 6.2 Guidance Document.’ 
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the patient unless agreed with AstraZeneca and appropriate 
labelling, shipment and containment provisions are approved. 
7.4 
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle. 
The Principal Investigator at each centre keeps full traceability of collected biological samples 
from the patients while in storage at the centre until shipment or disposal (where appropriate) 
and keeps documentation of receipt of arrival. 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival. 
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers. 
Samples retained for further use are registered in the AstraZeneca biobank system during the 
entire life cycle. 
7.5 
Withdrawal of informed consent for donated biological samples 
If a patient withdraws consent to the use of any optional donated biological samples, the 
samples will be disposed of/destroyed, and the action documented.  If samples are already 
analysed, AstraZeneca is not obliged to destroy the results of this research. 
The Principal Investigator: 

Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca 

Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented 

Ensures the laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed/destroyed, the action 
documented and the signed document returned to the study site 

Ensures that the patient and AstraZeneca are informed about the sample disposal. 


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AstraZeneca ensures the central and bioanalytical laboratories holding the samples are 
informed about the withdrawn consent immediately and that samples are disposed 
of/destroyed and the action documented and returned to the study site. 
8. 
ETHICAL AND REGULATORY REQUIREMENTS 
8.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples. 
8.2 
Patient data protection 
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation. 
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician or any other third party, unless 
required to do so by law. 
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an investigator might know a patient’s 
identity and also have access to his or her genetic data. Also Regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate. 
8.3 
Ethics and regulatory review 
An Ethics Committee should approve the final study protocol, including the final version of 
the Informed Consent Form and any other written information and/or materials to be provided 
to the patients.  The investigator will ensure the distribution of these documents to the 
applicable Ethics Committee, and to the study site staff. 
The opinion of the Ethics Committee should be given in writing. The investigator should 
submit the written approval to AstraZeneca before enrolment of any patient into the study.  
The Ethics Committee should approve all advertising used to recruit patients for the study. 
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements. 


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If required by local regulations, the protocol should be re-approved by the Ethics Committee 
annually. 
Before enrolment of any patient into the study, the final study protocol, including the final 
version of the Informed Consent Form, is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations. 
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities. 
AstraZeneca will provide Regulatory Authorities, Ethics Committees and Principal 
Investigators with safety updates/reports according to local requirements, including SUSARs 
(Suspected Unexpected Serious Adverse Reactions), where relevant. 
In the USA the Principal Investigator is also responsible for providing the Ethics Committee 
with reports of any serious and unexpected adverse drug reactions from any other study 
conducted with the investigational product.  AstraZeneca will provide this information to the 
Principal Investigator. 
Progress reports and notifications of serious and unexpected adverse drug reactions will be 
provided to the Ethics Committee according to local regulations and guidelines. 
8.4 
Informed consent 
The Principal Investigator(s) at each centre will: 

Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study 

Ensure each patient is notified that they are free to discontinue from the study at any 
time 

Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided 

Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study 

Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File 

Ensure a copy of the signed Informed Consent Form is given to the patient 

Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the informed consent form that is approved by an Ethics Committee 


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8.5 
Changes to the protocol and informed consent form 
Study procedures will not be changed without the mutual agreement of the International co-
ordinating Investigator and AstraZeneca. 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol). 
The amendment is to be approved by the relevant Ethics Committee and if applicable, also the 
national regulatory authority approval, before implementation.  Local requirements are to be 
followed for revised protocols. 
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s). For distribution to Ethics Committee see Section 8.3. 
If a protocol amendment requires a change to a centre’s Informed Consent Form, AstraZeneca 
and the centre’s Ethics Committee are to approve the revised Informed Consent Form before 
the revised form is used.  
If local regulations require, any administrative change will be communicated to or approved 
by each Ethics Committee. 
8.6 
Audits and inspections 
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification.  The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analysed, and accurately reported according to the protocol, Good Clinical 
Practice (GCP), guidelines of the International Conference on Harmonisation (ICH), and any 
applicable regulatory requirements.  The investigator will contact AstraZeneca immediately if 
contacted by a regulatory agency about an inspection at the centre. 
9. 
STUDY MANAGEMENT BY ASTRAZENECA 
9.1 
Pre-study activities 
Before the first patient is entered into the study, it is necessary for a representative of 
AstraZeneca to visit the investigational study site to: 

Determine the adequacy of the facilities 

Determine availability of appropriate patients for the study 

Discuss with the investigator(s) (and other personnel involved with the study) their 
responsibilities with regard to protocol adherence, and the responsibilities of 


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AstraZeneca or its representatives.  This will be documented in a Clinical Study 
Agreement between AstraZeneca and the investigator. 
9.2 
Training of study site personnel 
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and the WBDC 
system(s) utilised. 
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. 
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff). 
9.3 
Monitoring of the study 
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to: 

Provide information and support to the investigator(s) 

Confirm that facilities remain acceptable 

Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the CRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks 
are being performed 

Perform source data verification (a comparison of the data in the CRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent of participating patients. This 
will require direct access to all original records for each patient (eg, clinic charts) 

Ensure withdrawal of informed consent to the use of the patient’s biological 
samples is reported and biological samples are identified and disposed of/destroyed 
accordingly, and the action is documented, and reported to the patient 
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct. 
9.3.1 
Source data 
Refer to the Clinical Study Agreement for location of source data. 


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9.4 
Study agreements 
The Principal Investigator at each/the centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of patients and in all other respects, not relating to study conduct or treatment of 
patients, the terms of the Clinical Study Agreement shall prevail. 
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled. 
9.4.1 
Archiving of study documents 
The Investigator follows the principles outlined in the Clinical Study Agreement (CSA). 
9.5 
Study timetable and end of study 
The end of the study is defined as ‘the last visit of the last patient undergoing the study.’ All 
patients in this study will be followed for 3 years following their RAI treatment. 
The study is expected to start in 2013 and to end in 2017. 
The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or if recruitment is slow.  AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with selumetinib. 
10. 
DATA MANAGEMENT BY ASTRAZENECA OR DELEGATE 
Data entered in the WBDC system will be immediately saved to a central database and 
changes tracked to provide an audit trail. When the principal investigator has signed the eCRF 
electronically as per eCRF instructions, the subject’s data will be locked. 
Medical coding will be performed using the AstraZeneca Autocoder application.  The Data 
Management Centre Coding Team will perform coding using agreed coding conventions.  
AEs and medical and surgical history will be coded using the standard dictionary – Medical 
Dictionary for Regulatory Activities (MedDRA), and concomitant medication will be coded 
using the AstraZeneca Drug Dictionary. 
SAEs will be entered into a global patient safety database for regulatory reporting purposes 
and be reconciled with the AEs in the clinical database. 
Data associated with biological samples will be transferred to the data manager as an 
electronic file and merged with study data as appropriate. 


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Data from external providers (eg, central laboratory) will be validated as appropriate to ensure 
that it is consistent with the clinical data and included in the final database. 
Clean file will be declared for the database once all data have been received, entered, 
validated and all queries resolved.  The database will be locked after clean file has been 
declared.  Treatment codes will not be broken until after clean file.  Following database lock, 
all data will be extracted as SAS (Statistical Analysis Software) data sets for the statistical 
analysis to be performed by AstraZeneca.  
Any genotype data generated in this study will be stored in the AstraZeneca genotyping LIMS 
database, or other appropriate secure system within AstraZeneca and/or third party contracted 
to work with AstraZeneca to analyse samples.  The results from this genetic research may be 
reported in the CSR for the main study, or in a separate report as appropriate. Some or all of 
the clinical datasets from the main study may be merged with the genetic data in a suitable 
secure environment separate from the clinical database.  The results from this genetic research 
will be reported separately from the Clinical Study Report for the main study. 
11. 
EVALUATION AND CALCULATION OF VARIABLES BY 
ASTRAZENECA OR DELEGATE 
11.1 
Calculation or derivation of efficacy variable(s) 
11.1.1 
Complete remission rate at 18 months post-RAI treatment 
Patients will be considered to be in complete remission if they are alive and all of the criteria 
in Section 6.4.1 are met at 18 months post-RAI treatment. 
Complete remission rate at 18 months post-RAI treatment is defined as the proportion of 
patients who have achieved complete remission at this time point. The complete remission 
rate will be calculated using all randomized patients as the denominator.  
11.1.2 
Clinical remission rate at 18 months post-RAI treatment 
Patients will be considered to be in clinical remission if they are alive and all of the criteria in 
Section 6.4.6 are met at 18 months post-RAI treatment. 
Clinical remission rate at 18 months post-RAI treatment is defined as the proportion of 
patients who have achieved clinical remission at this time point. The clinical remission rate 
will be calculated using all randomized patients as the denominator. 
11.1.3 
Thyroid cancer recurrence 
The occurrence and date of any thyroid cancer recurrence will be recorded for patients who 
have previously entered either complete or clinical remission (at any point during the study or 
follow up periods). The rate of thyroid cancer recurrence will be calculated using only patients 
who have achieved remission as the denominator. 


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11.1.4 
Survival status 
The survival status and survival assessment date of all patients will be recorded. Survival time 
will be calculated as the time from the date of randomisation to the date of death. Patients who 
have not died at the time of the final study follow up will be censored at the last date the 
patient was known to be alive. 
11.1.5 
Further therapy 
The dates and type of any further therapy for thyroid cancer will be recorded during the study 
and follow up periods. 
11.2 
Calculation or derivation of safety variable(s) 
11.2.1 
Adverse events 
Adverse events will be listed for each patient and summarised by treatment received according 
to the System Organ Class (SOC) and preferred term assigned to the event using the 
MedDRA.  AEs will be graded according to the National Cancer Institute Common 
Terminology Criteria for AEs Version 4.  The CTC Grade will be assigned by the 
Investigator. 
AE summaries will include all of the following: 

Any AEs occurring after commencement of study treatment and within 30 days of 
the last dose of study medication 

AEs related to RAI or the combination of RAI and study treatment occurring 
between 30 days after the last dose of study medication and the final study visit at 3 
years following the initial RAI dose 

All SAEs occurring after commencement of study treatment until the final study 
visit at 3 years following the initial RAI dose 
AEs occurring before commencement of study treatment will not be included in AE 
summaries but will be included and identified in the patient listings. 
11.2.2 
Other significant adverse events (OAE) 
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and DAEs.  Based on the expert’s judgement, 
significant adverse events of particular clinical importance may, after consultation with the 
Global Patient Safety Physician, be considered OAEs and reported as such in the Clinical 
Study Report.  A similar review of laboratory/vital signs/ECG data will be performed for 
identification of OAEs. 
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction 
or significant additional treatment. 


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11.2.3 
Vital signs, laboratory data, ECGs, ECHO/MUGA, physical examination and 
ophthalmologic examination 
For change from baseline summaries for vital signs, laboratory data, ECGs, and physical 
examination, the baseline value will be the latest result obtained prior to the start of study 
treatment. 
QTcF (Fredericia) will be calculated programmatically by AstraZeneca using the reported 
ECG values (RR and QT). 
QTcF = QT / RR^ (1/3) where RR is in seconds 
The denominator used in laboratory summaries will only include evaluable patients, in other 
words those who had sufficient data to have the possibility of an abnormality. For example: 

If a CTCAE criterion involves a change from baseline, evaluable patients 
would have both a pre-dose and at least 1 post-dose value recorded 

If a CTCAE criterion does not consider changes from baseline, to be 
evaluable the patient need only have 1 post dose-value recorded 
The denominator in vital signs data should include only those patients with recorded data. 
11.3 
Calculation or derivation of PK variables 
The final PK analyses will be the responsibility of Clinical Pharmacology and 
Pharmacometrics, AstraZeneca. 
Using appropriate PK software the available PK data will be used to derive PK parameters 
such as, but not restricted to, Cmax, AUC for Selumetinib, N-desmethyl selumetinib and any 
other metabolites determined. 
The selumetinib, N-desmethyl selumetinib and metabolite concentration-time profiles, along 
with the derived PK variables, will be listed for each patient per dose and dosing day and 
summarised appropriately, as described in the SAP. 
Population PK models may be used to derive the PK parameters and will aim to characterise 
variability in the population by investigating the influence of covariates such as weight, age, 
sex, and/or concomitant medications.  In addition, if the data are suitable, potential 
relationships between plasma selumetinib and N-desmethyl selumetinib concentrations will be 
investigated using a graphical approach and/or appropriate PK/PD modelling techniques.  A 
detailed PK analysis plan will be produced prior to any such investigations and will be 
reported separately. 
11.4 
Calculation or derivation of pharmacogenetic variables 
Genetic data (except BRAF and NRAS data) will be reported separately to the CSR for this 
study. 


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11.5 
Calculation or derivation of biomarker variables  
11.5.1 
Analysis of NRAS and BRAF 
Tumour samples will be collected as outlined in the study plan and assessed for BRAF and 
NRAS mutational status (as detailed in section 6.10.1) to identify patients for this patient 
population. 
11.5.2 
Further biomarker research analysis 
Methods of analysis for all other biomarker research may include investigation of genetic 
variability, gene expression profiling, protein expression profiling. 
12. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
12.1 
Description of analysis sets 
12.1.1 
Intention to treat (ITT) analysis set 
The ITT analysis set will include all randomised patients. The ITT analysis set will be used for 
all efficacy analyses and treatment groups will be compared on the basis of randomised 
treatment, regardless of the treatment actually received. Patients who were randomised but did 
not subsequently go on to receive study treatment will be included in the ITT analysis set. 
12.1.2 
BRAF/NRAS mutation positive analysis set 
For the analysis of the BRAF and NRAS mutation positive population (secondary objective), 
only those patients from the ITT population with genetic samples that are positive for BRAF 
or NRAS will be included. 
12.1.3 
Treatment-compliant (TC) analysis set 
The treatment-compliant analysis set will be a subset of the ITT population containing patients 
that adhered to the minimum study treatment requirements specified in Section 3.1.1, i.e. 
patients who take study treatment twice daily for a minimum of 7 consecutive days prior to 
RAI therapy, on the day of RAI therapy, and for 5 consecutive days afterwards. Patients must 
also have had their RAI dose.  
The TC analysis set will be used as a sensitivity analysis for the primary endpoint. 
12.1.4 
Safety analysis set 
The safety analysis set will consist of all patients who received at least one dose of 
randomised treatment. Safety data will not be formally analysed but summarised using the 
safety analysis set, according to the treatment combination received, ie, erroneously treated 
patients (eg, those randomised to treatment A but actually given treatment B) will be 
summarised according to the treatment they actually received. 


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12.1.5 
PK analysis set 
PK data will be analysed according to treatment received.  This population will comprise all 
patients who receive study treatment as per protocol and do not violate or deviate from the 
protocol in ways that would significantly affect the PK analyses.  The population will be 
defined by the AstraZeneca Study Team Physician, Pharmacokineticist and Statistician prior 
to any analyses being performed. 
12.2 
Methods of statistical analyses 
A comprehensive SAP will be prepared prior to start of recruitment (first subject in).  
Since there is only one primary endpoint/comparison of interest (complete remission rate at 18 
months for selumetinib vs. placebo in the ITT population) the primary endpoint will be 
considered statistically significant if the two-sided p-value is less than 0.05.  
12.2.1 
Complete remission rate at 18 months post-RAI treatment 
The primary endpoint of complete remission rate at 18 months will be compared between 
selumetinib in combination with RAI, and placebo in combination with RAI in the ITT 
population using a logistic regression model including treatment as the only covariate. Results 
will be presented in terms of the odds ratio, 95% confidence interval and associated p-value. A 
sensitivity analysis will be performed using a logistic regression model including treatment 
and adjusted for the covariates histology status (papillary, follicular, poorly differentiated), 
mutation status (BRAF/NRAS positive, BRAF/NRAS not detected) and age, provided there are 
enough data points for a meaningful analysis.  
A secondary analysis of complete remission rate will be performed to compare selumetinib in 
combination with RAI vs. placebo in combination with RAI in the BRAF/NRAS mutation 
positive population using a logistic regression model including treatment as the only covariate.  
A sensitivity analysis will be performed using a logistic regression model adjusted for the 
covariates histology status (papillary, follicular, poorly differentiated) and age, provided there 
are enough data points for a meaningful analysis. 
For the sensitivity analyses using each covariate adjusted logistic regression models, the 
following missing data approach for each covariate will be adopted: 

Missing age; impute the mean of observed ages 

Missing histology status; add an additional ‘unknown’ category to make 4 
categories (papillary, follicular, poorly differentiated, and unknown) 

Missing mutation status; add an additional ‘unknown’ category to make 3 
categories (BRAF/NRAS positive, BRAF/NRAS not detected and unknown) 
The results of the analyses, in terms of treatment effects, will be presented as odds ratios 
together with their associated 95% profile likelihood confidence intervals and 2-sided p-
values. The p-value will be based on twice the change in log-likelihood resulting from the 


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addition of a treatment factor to a model that contains the covariates defined above. The 
complete remission rate and 95% confidence interval will be estimated for each treatment 
arm. 
Sensitivity analyses for the primary endpoint 
The primary endpoint analysis, a logistic regression model including treatment as the only 
covariate for complete remission rate at 18 months, will be repeated:  

using the treatment-compliant population. 

to allow patients that were identified as being in complete remission outside of the 
specified time windows to be classed as being in complete remission, in order to 
investigate time bias between arms.  

excluding patients with high TSH. Elevated TSH can be caused by poor compliance 
and can mean a patient is less likely to achieve remission, therefore this sensitivity 
analysis excludes patients with high TSH, which is defined as a value >10 mIU/L 
recorded at any point by standardised central laboratory analysis. 
Treatment by covariate interactions 
The extent to which the treatment effect is consistent across the subgroups histology status, 
mutation status (ITT population only), gender, race and age will be assessed in the ITT 
population and in the BRAF/NRAS mutation positive population. The presence of a 
quantitative interaction will be assessed by means of an overall global interaction test. This 
will be performed by comparing the fit (likelihood ratio test) of a model including all 
covariate-by-randomised treatment interaction terms, treatment and covariate terms with a 
model that excludes the interaction terms. If the global interaction test is found to be 
statistically significant at the 10% significance level, an attempt to determine the cause and 
type of interaction will be made. Stepwise backward selection will be performed on the 
saturated model, whereby (using a 10% level throughout) the least significant interaction 
terms are removed one-by-one and any newly significant interactions re-included until a final 
model is reached where all included interactions are significant and all excluded interactions 
are non-significant.  Throughout this process all main effects will be included in the model 
regardless of whether the corresponding interaction term is still present.  This approach will 
identify the factors that independently alter the treatment effect and prevent identification of 
multiple correlated interactions. 
For quantitative interactions identified, the presence of any qualitative interactions will be 
assessed using the approach of Gail and Simon (Gail & Simon 1985). For categorical 
covariates the test statistics, based on the appropriate degrees-of-freedom, can be taken 
directly from the paper. For the continuous covariate, the approach will be adapted as follows:  
Identify the cut-point (-1/3) of the covariate where the odds ratio for the treatment effect is 
1, where 1 is the treatment parameter estimate and 3 is the treatment-by-covariate parameter 


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estimate. Re-analyse the data separately for the values of the covariate above and below the 
cut-point and use the separate chi-square values in the Simon and Gail test. 
Subgroup data 
Subgroup data (histology status, BRAF or NRAS mutation status, gender, race and age) will be 
summarised by a forest plot where the odds ratio is plotted on the log scale. For this, age will 
be categorised as 45 or >45 years. The treatment effect and 95% confidence intervals for 
each level of the subgroup will be obtained from a single logistic regression model that 
contains a treatment, factor and treatment-by-factor interaction term.  
12.2.2 
Clinical remission rate at 18 months post-RAI treatment 
The secondary endpoint of clinical remission rate will be analysed as described in Section 
12.2.1, except for primary endpoint specific sensitivity analyses and treatment by covariate 
interaction testing. 
12.2.3 
Thyroid cancer recurrence 
Very few thyroid cancer recurrences are expected on this study, therefore no formal analysis 
of thyroid cancer recurrence data will be performed; data will be listed and summarised.  
12.2.4 
Survival status 
Very few deaths are expected on this study therefore no formal analysis of survival data will 
be performed; data will be listed and summarised. Kaplan-Meier plots of survival may 
produced if appropriate.  
12.2.5 
Further therapy 
No formal analysis of further therapy data will be performed; data will be listed and 
summarised. Kaplan-Meier plots of time to further therapy may produced if appropriate. 
12.2.6 
Safety data analysis 
Safety data will not be formally analysed. All patients who commenced study treatment will 
be included in the assessment of safety and will be summarised by treatment received. 
12.2.7 
PK data analysis 
The selumetinib, N-desmethyl selumetinib and metabolite concentration-time profiles, along 
with the derived PK variables, will be listed for each patient per dose and dosing day and 
summarised appropriately. 
12.2.8 
Genetics 
Any genetic data analysis (other than BRAF and NRAS) will be reported outside the CSR for 
this study. 


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12.2.9 
Biomarker data 
BRAF and NRAS mutation assessment of tumour biopsy will be used to identify patients for 
this primary patient population.  
The results of any other exploratory biomarker investigations will be reported outside of the 
CSR. 
12.2.10 
Interim analyses 
There are no interim analyses planned for this study.  
12.3 
Determination of sample size 
The sample size for this study was selected to be consistent with the research hypothesis as 
described in Section 1.2. 
The primary objective of the study is to compare the efficacy of selumetinib with RAI versus 
placebo with RAI, by assessment of the complete remission rate at 18 months post-RAI 
treatment in the ITT study population. Assuming the true complete remission rates in the 
overall study population are 30% and 50% for the placebo and selumentinib-containing arms, 
respectively, a total of 228 patients, randomised in a 2:1 ratio (152 and 76 patients in the 
selumentinib and placebo-containing arms, respectively) provides at least 80% power to show 
statistical significance, based on a two-sided 5% significance level. 
12.4 
Data monitoring committee  
Due to the short treatment duration in this study there will not be a data monitoring committee 
for this study. 


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13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED 
BY THE INVESTIGATOR 
13.1 
Medical emergencies and AstraZeneca contacts 
The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study. A medical emergency usually 
constitutes an SAE and is to be reported as such, see Section 6.5.4 
In the case of a medical emergency the investigator may contact the Study Delivery Team 
Physician. If the Study Delivery Team physician is not available, contact the Study Delivery 
Team Leader. 
Name  
Role in the study  
Address & telephone number 
 
AstraZeneca Physician 
responsible for the protocol at 
central R&D site 
 
 
 
 
 
 
 
 
 
AstraZeneca Study Delivery 
Team Leader responsible for 
the protocol at central R&D 
site 
 
 
 
 
 
 
 
 
24-hour emergency cover at central 
R&D site. 
24-hour emergency cover at 
central R&D site.  
 
 
 
 
 
13.2 
Overdose  
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the relevant 
AE modules in the CRF and on the Overdose CRF module. 
An overdose without associated symptoms is only reported on the Overdose CRF module. 
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If an overdose on an AstraZeneca study drug occurs in the course of the study, then 
investigators or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site. 
For overdoses associated with SAE, standard reporting timelines apply, see Section 6.5.4.  For 
other overdoses, reporting should be done within 30 days. 
13.3 
Pregnancy 
All outcomes of pregnancy should be reported to AstraZeneca. 
13.3.1 
Maternal exposure 
If a subject becomes pregnant during the course of the study, investigational product should be 
discontinued immediately. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication.  Congenital abnormalities/birth defects and spontaneous 
miscarriages should be reported and handled as SAEs.  Elective abortions without 
complications should not be handled as AEs.  The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should be followed up and documented even if the subject was discontinued from the study. 
If any pregnancy occurs in the course of the study, then investigators or other site personnel 
inform appropriate AstraZeneca representatives immediately, or no later than 24 hours of 
when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
days for SAEs, see Section 6.5.4 and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is used 
to report the outcome of the pregnancy. 
13.3.2 
Paternal exposure 
The outcomes of any conception occurring from the date of the first dose, until 30 days after 
last dose, must be followed up and documented in the “Pregnancy Outcome Report” form. 
Male patients must refrain from fathering a child for 12 weeks following the last dose of study 
treatment, since the potential for chromosomal aberrations in male gametes, and possible 
teratogenic effects thereof, has not yet been thoroughly investigated. Restrictions from 


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fathering children should also take into account local recommendations following therapy 
with RAI. 
Pregnancy of the patients’ partner is not considered to be an AE.  However, the outcome of all 
pregnancies (including spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented. 
14. 
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Association Staging System. Thyroid. 2010; 20(12): 1341-9. 
Vaisman et al, 2011 
Vaisman F, Tala H, Grewal R, Tuttle RM. In differentiated thyroid cancer, an incomplete 
structural response to therapy is associated with significantly worse clinical outcomes than 
only an incomplete thyroglobulin response. Thyroid. 2011;21(12):1317-22. 
Vaisman et al 2012 
Vaisman F, Momesso D, Bulzico DA, Pessoa CHCN, Dias F, Corbo R, Vaisman M, Tuttle 
RM. Spontaneous remission in thyroid cancer patients after biochemical incomplete response 
to initial therapy. Clinical Endocrinology. 2012:76(3). 
 


Clinical Study Protocol Appendix B 
 
Drug Substance 
Selumetinib (AZD6244) 
 
Study Code 
D1532C00065
 
Edition Number 
1
 
Date 
24th January 2013 
Appendix B 
Additional Safety Information 


Clinical Study Protocol Appendix B 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Edition Number 1 
Date 24th January 2013 
2(3)
FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS 
ADVERSE EVENT (SAE) 
Life threatening 
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure). 
Hospitalisation 
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 
Important medical event or medical intervention 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used. 
Examples of such events are:

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine 

Intensive treatment in an emergency room or at home for allergic bronchospasm 

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation 

Development of drug dependency or drug abuse. 


Clinical Study Protocol Appendix B 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Edition Number 1 
Date 24th January 2013 
3(3)
A GUIDE TO INTERPRETING THE CAUSALITY QUESTION 
The following factors should be considered when deciding if there is a “reasonable 
possibility” that an AE may have been caused by the drug. 

Time Course.  Exposure to suspect drug.  Has the subject actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug? 

Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? OR could the AE be anticipated from its pharmacological 
properties? 

Dechallenge experience.  Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug? 

No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors. 

Rechallenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support 
a rechallenge. 

Laboratory tests.  A specific laboratory investigation (if performed) has confirmed 
the relationship? 
A “reasonable possibility” could be considered to exist for an AE where one or more of these 
factors exist. 
In contrast, there would not be a “reasonable possibility” of causality if none of the above 
criteria apply or where there is evidence of exposure and a reasonable time course but any 
dechallenge (if performed) is negative or ambiguous or there is another more likely cause of 
the AE. 
In difficult cases, other factors could be considered such as: 

Is this a recognised feature of overdose of the drug? 

Is there a known mechanism? 
Ambiguous cases should be considered as being a “reasonable possibility” of a causal 
relationship unless further evidence becomes available to refute this.  Causal relationship in 
cases where the disease under study has deteriorated due to lack of effect should be classified 
as no reasonable possibility. 


Clinical Study Protocol Appendix C 
 
Drug Substance 
Selumetinib (AZD6244) 
 
Study Code 
D1532C00065
 
Edition Number 
1
 
Date 
24th January 2013 
Appendix C 
International Airline Transportation Association (IATA) 6.2 Guidance 
Document 


Clinical Study Protocol Appendix C 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065  
Edition Number 1
Date 24th January 2013 
2(3)
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES 
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories (http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.
htm).  For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005).  Infectious substances are now classified either as Category A, Category B or Exempt.  
There is no direct relationship between Risk Groups and categories A and B. 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus: 

are to be packed and shipped in accordance with IATA Instruction 602. 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name: 

UN 3373 – Biological Substance, Category B 

are to be packed in accordance with UN3373 and IATA 650 
Exempt - all other materials with minimal risk of containing pathogens 

Clinical trial samples will fall into Category B or exempt under IATA regulations 

Clinical trial samples will routinely be packed and transported at ambient 
temperature in IATA 650 compliant packaging 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.
htm)

Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as 
applicable 

Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times.  The IATA 650 biological sample 


Clinical Study Protocol Appendix C 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065  
Edition Number 1
Date 24th January 2013 
3(3)
containment standards are encouraged wherever possible when road or rail transport 
is used. 


Clinical Study Protocol Appendix D 
 
Drug Substance 
Selumetinib (AZD6244) 
 
Study Code 
D1532C00065
 
Edition Number 
1
 
Date 
24th January 2013 
Appendix D 
Actions Required in Cases of Combined Increase of Aminotransferase and 
Total Bilirubin - Hy’s Law  


Clinical Study Protocol Appendix D 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065  
Edition Number 1 
Date 24th January 2013 
2(4)
1. 
ACTIONS REQUIRED IN CASES OF AST OR ALT  3X ULN 
OR TBL  2X ULN 
The Investigator is responsible for, without delay, determining whether the subject meets 
potential Hy’s law (PHL) criteria; Aspartate Aminotransferase (AST) or Alanine 
Aminotransferase (ALT)  3x Upper Limit of Normal (ULN) and Total Bilirubin (TBL) 
2xULN at any point during the study, irrespective of Alkaline Phosphatase (ALP). The AST 
or ALT and total bilirubin values do not have to be elevated at the same visit or within any 
specified timeframe. 
1.1 
Identification 
In cases of AST or ALT  3x ULN or TBL  2x ULN, please follow the instructions below.  

Review each laboratory report and if a subject has an increase in AST or ALT 
3xULN or TBL  2xULN at any visit: 

Notify the AstraZeneca representative 

Promptly enter the laboratory date into the laboratory CRF. 
1.2 
Determination and Follow-up 
1.2.1 
Potential Hy’s Law Criteria not met 
If the subject has not had AST or ALT  3xULN and TBL  2xULN at any point in the study 
even if on different visits, irrespective of ALP 

Inform the AZ representative that the subject has not met PHL criteria 

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the CSP. 
1.2.2 
Potential Hy’s Law Criteria met 
If the subject has had AST or ALT  3xULN and TBL  2xULN at any point in the study 
even if on different visits, irrespective of ALP:  

Notify the AZ representative who will then inform the central ST 
The Study Physician (SP) contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study subject’s follow-up and the continuous review of data. 


Clinical Study Protocol Appendix D 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065  
Edition Number 1 
Date 24th January 2013 
3(4)
The Investigator: 

Follows the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated.

Investigates the etiology of the event and perform diagnostic investigations as 
discussed with the SP 

Completes the Liver CRF Modules.  

If at any time (in consultation with the SP) the PHL case meets serious criteria, it 
should be reported as an SAE using standard reporting procedures. 
1.3 
Review and Assessment 
No later than 3 weeks after the biochemistry abnormality was initially detected,  the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for the elevations in liver biochemistry other than Drug 
Induced Liver Injury (DILI) caused by the Investigational Medicinal Product (IMP). 
For the purpose of this process a Hy’s Law case is defined as: 
Any subject with an increase in both Aspartate Aminotransferase (AST) or Alanine 
Aminotransferase (ALT)  3x Upper Limit of Normal (ULN) and Total Bilirubin (TBL) 
2xULN, where no other reason can be found to explain the combination of increases, eg, 
elevated serum Alkaline Phosphatase (ALP) indicating cholestasis, viral hepatitis, another 
drug 
If there is an agreed alternative explanation for the AST or ALT and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE.  

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF. 

If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly and follow the AZ standard processes. 
If it is agreed that there is no other explanation that would explain the AST or ALT and TBL 
elevations: 

Report an SAE (report term Hy’s Law’) according to AZ standard processes.  

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply 


Clinical Study Protocol Appendix D 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065  
Edition Number 1 
Date 24th January 2013 
4(4)

As there is no alternative explanation for the HL case, a causality assessment of 
related should be assigned. 
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for a HL case, then it is assumed that there is 
no alternative explanation until such time as an informed decision can be made: 

Report an SAE (report term ’Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above 
2. 
REFERENCES 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’: 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm06499
3.htm


Clinical Study Protocol Appendix E 
 
Drug Substance 
Selumetinib (AZD6244) 
 
Study Code 
D1532C00065
 
Edition Number 
1
 
Date 
24th January 2013 
Appendix E 
Cockcroft-Gault Formula 


Clinical Study Protocol Appendix E 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Edition Number 1 
Date 24th January 2013 
2(2)
COCKCROFT-GAULT FORMULA 
The Cockcroft-Gault formula has been provided for reference, as the protocol allows for the 
serum creatinine clearance to be calculated using the Cockcroft-Gault formula (see Section 
4.1, Inclusion criteria):  
For serum creatinine values in mol /L: 
Estimated creatinine clearance rate (eCCr) (for men) = [(140 – age) x weight (kg) x 1.23] / 
creatinine (mol/L) 
eCCr (for women) = [(140 – age) x weight (kg) x 1.04] / creatinine (mol/L) 
For serum creatinine values in mg/dL: 
eCCr (for men) = [140 – age] x weight (kg) / [72 x creatinine (mg/dL)] 
eCCr (for women) = 0.85 x ([140 – age] x weight (kg) / [72 x creatinine (mg/dL)]) 
Reference: Cockcroft D, Gault MD. Nephron 16: 31-41, 1976. 


Clinical Study Protocol Appendix F 
 
Drug Substance 
Selumetinib (AZD6244) 
 
Study Code 
D1532C00065
 
Edition Number 
1
 
Date 
24th January 2013 
Appendix F 
Low Iodine Diet 


Clinical Study Protocol Appendix F 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Edition Number 1 
Date 24th January 2013 
 
2(10)
LOW IODINE DIET  
Published data and opinion regarding the necessity for a low iodine diet prior to RAI therapy 
or a diagnostic whole body scan is variable.  For the purpose of this study a low iodine diet 
will be mandated in order to standardise patient care and study data as best as possible. 
Compliance to a low iodine diet will not be recorded or assessed, and all randomised patients 
will receive RAI treatment as planned. 
A low iodine diet is necessary at two occasions in the study: 
Prior to RAI adjuvant treatment 
All patients must be willing to adhere to a low iodine diet for a period of 1 week before their 
planned RAI adjuvant treatment, until the day after their RAI therapy. 
Prior to the primary endpoint Stage 2 assessments 
All patients must be willing to adhere to a low iodine diet for a period of 1 week before the 
diagnostic 131I dose used prior to the primary endpoint WBS assessment (131I nuclear medicine 
scan), until the diagnostic WBS assessment is completed. This is only relevant for patients 
who progress to Stage 2 primary endpoint assessments (refer to Section 6.4.2 of the main 
protocol).
What is Iodine?
Iodine is a mineral. It plays an important role in several processes that take place in the body. 
One is the production of a hormone called thyroxine, which occurs in the thyroid gland.  
Where is Iodine Found?  
The amount of iodine found in food varies. Much of the iodine we get comes from iodized salt 
and breads. Adults need 150 micrograms of iodine a day. This appendix describes an example 
of a low iodine diet typically used in this treatment setting. This is a diet with less than 50 
micrograms of iodine per day. A local low iodine diet may be used instead, as long as it is 
equivalent to this appendix. 
Why is a Low Iodine Diet Necessary?  
The iodine in your diet can block the uptake of radioactive iodine by the thyroid gland.  
What Should You Avoid?  
Read all food labels to check for iodine content. Do NOT eat or use:  

Iodized salt.  

Sea salt in any form.  

Onion salt.


Clinical Study Protocol Appendix F 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Edition Number 1 
Date 24th January 2013 
 
3(10)

Celery salt.  

Garlic salt.  

Seasoned salt.

Kelp (seaweed).  

Any food that has: 

Iodates

Iodides  

Algin 

Alginates

Carrageen  

Agar

Commercial breads and bakery products, because they often contain iodate.  

Milk (except for 1 ounce a day), egg yolks, and seafood.  

Vitamins and food supplements if they have iodine. If you have any doubt, do not 
take them.

Food, pills, or capsules with food dyes or that are orange, red, or brown in color. 
Examples include red or pink cereals or candies/sweets.  

Antiseptics, such as tincture of iodine (Betadine®) applied on a cut.  

Cough medicines (especially those with red coloring).  

Supplements such as:

Ensure
®

Boost
®

Commercial shakes  

Nutrament
®.


Clinical Study Protocol Appendix F 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Edition Number 1 
Date 24th January 2013 
 
4(10)

Restaurant and processed foods, because they are often high in iodine content.  

Soy products such as edamame, tofu, soy burgers etc.  

All canned foods, because the lining of the can contains iodine.  
Do not stop taking any of your medicines unless your doctor tells you. 
Ask your doctor about drinking alcohol during a low iodine diet.  
This low iodine diet does not meet the suggested daily allowance for all nutrients. You will be 
on it for a short time only.  
Drink Plenty of Fluids  
Note: Unless your doctor tells you differently, you must drink at least 8 to 10, 8-ounce 
cups of fluid a day. This includes the drinks in the diet guidelines and as much water as 
you want.  


Clinical Study Protocol Appendix F 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Edition Number 1 
Date 24th January 2013 
 
5(10)
LOW IODINE DIET GUIDELINES  
Breads and Cereals  
Total number of servings per day: 6-8  
(1 serving equals 1 slice of bread or 1/2 cup of cooked pasta) 
Include  
Plain cooked barley, oats, millet, buckwheat, 
bulgur wheat, quinoa; unsalted unprocessed 
preservative-free boxed cereals such as 
puffed rice and shredded wheat; rice, plain 
macaroni, spaghetti, noodles; unsalted grits, 
cream of rice or cream of wheat hot cereals; 
unsalted rice cakes, unsalted plain crackers, 
English muffins, plain unsalted popcorn, 
homemade breads prepared without 
commercial dough.  
Avoid
All commercial breads and rolls, processed 
boxed cereals, salted crackers, potato 
chips/crisps, pretzels, bagels, Melba toast, 
egg noodles, packaged rice and pasta mixes.  
Meat and Meat Substitutes 
Total number of servings per day: Two–three
(1 serving equals 3 ounces of meat, fish, poultry, or 2 Tablespoons of unsalted peanut or 
almond butter)
Include 
Fresh beef, veal, pork, lamb, chicken and 
turkey; unsalted peanut or almond butter; 
freshwater fish such as carp, riverbass, lake 
trout, and river perch; fresh egg white.  
Avoid
Egg yolks and whole eggs, foods made with 
eggs; all fast foods; all canned fish such as 
salmon and tuna; seafood, shellfish (clams, 
crabs, oysters, lobsters), or any food made 
with fish stock; all processed meats; liver and 
all organ meats; all canned, dried, salted, or 
cured meats such as bacon, sausage, ham, 
frankfurters, chipped beef, luncheon meats 
(salami, bologna, pastrami); spicy meats such 
as chili, beef jerky, liverwurst; all canned or 
processed poultry such as turkey or chicken 
roll; tofu and soy products, such as soy 
burgers (e.g., Boca); salted peanut butter.  


Clinical Study Protocol Appendix F 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Edition Number 1 
Date 24th January 2013 
 
6(10)
Milk and Milk Products 
Total number of servings per day: Zero
Include  
None allowed 
Exception: Only 1 ounce of milk a day in 
your coffee or tea.
Avoid
All milk (except for one ounce daily) and 
milk products such as condensed or 
evaporated milk, cheese, yogurt, puddings, 
ice cream, custard; any cream such as 
heavy/double or light/single cream, whipped 
cream, sour cream; any foods made with 
cream or milk or cheese such as soup, pizza, 
macaroni and cheese.
Fruits 
Total number of servings per day: Five 
(1 serving equals 1 small piece of fruit or 3/4 cup of juice)
Include  
All fresh fruit, exception: limit bananas to 1 
serving per day; fresh apple sauce; all natural 
frozen fruits; fresh fruit juices (including 
bottles or cartons of fruit juice without 
artificial coloring or preservatives); white 
grape juice.  
Avoid
Cranberries, all dried fruits, all canned fruits 
and canned fruit juices; jarred applesauce; 
cranberry and grape juice, canned or bottled 
cherries; rhubarb.  


Clinical Study Protocol Appendix F 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Edition Number 1 
Date 24th January 2013 
 
7(10)
Vegetables
Total number of servings per day: Four 
(1 serving equals 1/2 cup of cooked or 1 cup raw vegetable)
Include  
All fresh vegetables except spinach, fresh 
potatoes without skin, all plain frozen 
vegetables without added salt, fresh or dried 
lentils and peas.  
Avoid
All canned vegetables and all canned 
vegetable juices, fresh or dried beans such as 
red kidney beans, lima beans, navy beans, 
pinto beans; canned legumes (such as beans, 
peas, and lentils); canned soups; sauerkraut, 
celery; commercially prepared potatoes (e.g., 
instant mashed potatoes); frozen vegetables 
with added salt; spinach.  
Fat 
Total number of servings per day: 
Suggest four to six servings a day 
(1 serving equals 1 teaspoon of butter or oil)
Include  
Unsalted margarine or sweet butter (not
more than 1 teaspoon of each per day), 
oils, vegetable shortening, plain oil and 
white vinegar dressing.  
Avoid
Salted nuts and seeds, mayonnaise, 
commercial salad dressings and salad cream, 
and lard.


Clinical Study Protocol Appendix F 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Edition Number 1 
Date 24th January 2013 
 
8(10)
Beverages
Total number of servings per day: No restrictions 
One serving equals 12 ounces of a carbonated beverage or 1 cup (8 ounces) of any of the other 
beverages listed
Include  
Water; bottled carbonated beverages without 
added coloring (such as Sprite®, 7Up®, 
sodium-free seltzer); brewed coffee, tea 
steeped from tea leaves; white tea bags; fresh 
lemonade or fresh orangeade.  
Avoid
Mineral water containing sodium; all bottled, 
canned, or powdered: iced tea, lemonade, 
instant coffee, instant tea, instant iced-tea, 
fruit punch, and other powdered or 
commercial drinks, such as Hi-C® and Kool-
Aid®; tea steeped from tea bags; soy milk 
and rice milk (which contain sea salt); ginger 
ale, Coke®, Pepsi® or any other carbonated 
beverages with added coloring.  
Desserts and sweets 
Total number of servings per day: Two 
(See below for serving equivalents)
Include 
Each of the following equals 1 serving:  

1 cup Knox® or equivalent clear 
gelatin  

2 tablespoons (T) sugar  

2T honey  

2T maple syrup  

2 regular size marshmallows  

1/2 cup natural sorbets with no 
coloring or added salt
Avoid
All bakery products such as pies, cakes, 
pastries, danishes, muffins, doughnuts and 
cookies; sweet crackers/biscuits; Jell-O® (or 
equivalent jelly), colored gelatins; chocolate 
and chocolate desserts; candy.  


Clinical Study Protocol Appendix F 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Edition Number 1 
Date 24th January 2013 
 
9(10)
Miscellaneous 
Total number of servings per day: Unlimited
Include  
Pepper, spices such as cinnamon; herbs 
such as oregano; white vinegar, and non-
iodized salt (contains trace amounts of 
iodine, use sparingly).  
Avoid
All salted foods such as salted nuts, Chinese 
food, soy sauce, catsup, Worcestershire sauce, 
chili sauce, all commercial sauces, tomato 
sauce, all gravies, olives, pickles, relish, 
bouillon cubes, soup bases, iodized salt, sea 
salt, onion salt, garlic salt, celery salt, seasoned 
salt, kelp (seaweed); molasses; any food 
containing food coloring, iodates, iodides, 
iodate dough conditioners or stabilizers, algin, 
alginate, carrageens, agar, or nori (seaweed); 
all sushi; red wine vinegar, balsamic vinegar 
(with caramel coloring); all additives, 
preservatives, or artificial colorings.  


Clinical Study Protocol Appendix F 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065 
Edition Number 1 
Date 24th January 2013 
 
10(10)
EXAMPLE MENU FOR A LOW IODINE DIET  
BREAKFAST  
1 Fruit  
 
1⁄2cup orange juice
3 Breads  
 
1⁄2 cup oatmeal (no milk) 1-2 plain unsalted cracker/crispbreads 
1 Meat  
 
1 egg white omelet  
Misc.   
 
2 teaspoons sugar
1 Beverage  
 
1 cup brewed coffee  
MID MORNING SNACK  
1 Bread  
 
2 rice cakes  
1 Fat   
 
1 teaspoon unsalted butter
1 Beverage  
 
1 cup water 
LUNCH  
1 Meat  
 
3 oz fresh turkey breast  
2 Fats   
 
2 tsp oil
2 Breads  
 
2 slices homemade white bread  
1 Vegetable   
1 cup Romaine lettuce  
1 Beverage  
 
1 cup fresh lemonade  
MID AFTERNOON SNACK  
1 Fruit  
 
1 fresh apple  
1 Meat  
 
2 tablespoons unsalted peanut butter
DINNER  
1 Meat  
 
3 oz roast beef 
2 Breads  
 
1 baked potato (no skin)  
2 Vegetables   
1 cup fresh broccoli  
2 Fats   
 
2 tsp oil (used in cooking)
1 Fruit  
 
1 orange  
1 Beverage  
 
1 cup white tea
BEDTIME SNACK  
1 Fruit  
 
1 small pear
1 Beverage  
 
1 cup tea made from fresh tea leaves  


Clinical Study Protocol Appendix G 
 
Drug Substance 
Selumetinib (AZD6244) 
 
Study Code 
D1532C00065
 
Edition Number 
1
 
Date 
24th January 2013 
Appendix G 
Guidance for Management of Adverse Events in Studies of Selumetinib  


Clinical Study Protocol Appendix G 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065  
Edition Number 1 
Date 24th January 2013 
2(10)
TABLE OF CONTENTS 
PAGE
TABLE OF CONTENTS.........................................................................................2
1. 
GUIDANCE FOR THE MANAGEMENT OF PATIENTS WITH RASH ............3
2. 
GUIDANCE FOR MANAGEMENT OF PATIENTS WITH VISUAL 
SYMPTOMS............................................................................................................5
3. 
RECOMMENDATIONS FOR DIARRHOEA MANAGEMENT..........................6
3.1 
Initial management of uncomplicated Grade 1 or 2 diarrhoea.................................7
3.2 
Management of persistent (>24h) Grade 1 or 2 diarrhoea despite 
loperamide at high dose ...........................................................................................7
3.3 
Management of any grade uncontrolled or complicated diarrhoea, or Grade 
3-4 diarrhoea ............................................................................................................7
4. 
RECOMMENDATIONS FOR INVESTIGATIONS OF PATIENTS 
WITH A NEW OR WORSENING DYSPNOEA .................................................10
 LIST OF TABLES 
Table 1 
Example topical steroids and antibiotics (use according to local 
guidelines) ..................................................................................................4 
Table 2 
CTCAE (version 4) grading for diarrhoea..................................................6
 LIST OF FIGURES 
Figure 1 
Guidance for the management of patients with diarrhoea..........................9


Clinical Study Protocol Appendix G 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065  
Edition Number 1 
Date 24th January 2013 
3(10)
1. 
GUIDANCE FOR THE MANAGEMENT OF PATIENTS WITH 
RASH
‡ selumetinib or matching placebo 
Version: Final 2.0 28Sep2012 


Clinical Study Protocol Appendix G 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065  
Edition Number 1 
Date 24th January 2013 
4(10)
Table 1 
Example topical steroids and antibiotics (use according to local 
guidelines) 
Topical steroids moderate strength 
Triamcinolone acetonide 0.025% 
Fluticasone proprionate 0.05% 
Desonide 0.05% 
Aclometasone 0.05% 
Topical antibiotics 
Clindamycin 1 - 2% 
 
 
Metronidazole 1% 
 
  
Erythromycin 1% - 2% 
Silver sulphadiazine 1%   
Oral antibiotics 
Doxycycline 100 mg bd 
Minocycline 100 mg bd 
Oxytetracycline 500 mg bd 


Clinical Study Protocol Appendix G 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065  
Edition Number 1 
Date 24th January 2013 
5(10)
2. 
GUIDANCE FOR MANAGEMENT OF PATIENTS WITH VISUAL SYMPTOMS 


Clinical Study Protocol Appendix G 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065  
Edition Number 1 
Date 24th January 2013 
6(10)
3. 
RECOMMENDATIONS FOR DIARRHOEA MANAGEMENT 
Diarrhoea may occur during treatment with selumetinib (AZD6244) and action should be 
taken as soon as symptoms develop.  The recommendations for diarrhoea management are 
based on guidelines from the American Society of Clinical Oncology (J Clin Oncol 2004; 
22:2918-26).  These guidelines recommend that treatment-induced diarrhoea should be 
carefully monitored and treated aggressively to ensure that severe complications are avoided 
and that treatment is not delayed.  

Patients should be made aware that they may experience diarrhoea and be 
encouraged to record the number of stools and report possible associated symptoms 

Patients should be given loperamide (in accordance with local regulation and local 
practice) to take home with them and be advised to start immediately after the first 
episode of unformed stool. 

Patients should be given dietary advice in case of diarrhoea (eg. BRAT [bananas, 
rice, apple sauce, toast, plain pasta] diet; readily digestible food; avoidance of 
lactose-containing products, fried, fatty or spicy food) and increase fluid intake (8 to 
10 glasses of clear fluids daily, including water and fluids containing salt and sugar, 
such as sports drinks and clear broth). 

Patients should seek advice early, from their physician or study nurse, if: 
(a) 
Persistent Grade 1 or 2 diarrhoea (refer to Section 3.2), or 
(b) 
Grade 3 or 4 diarrhoea, or 
(c) 
Diarrhoea becomes complicated by associated vomiting or inability to take 
oral fluids; marked abdominal distension or cramping; bloody stools, fever or 
symptoms of hypotension. 
Table 2 
CTCAE (version 4) grading for diarrhoea 
CTCAE
Grade 
Patients without colostomies 
Patients with colostomies 
Grade 1 
Increase in number of stools per 
day (<4) 
Mild increase in loose watery colostomy output 
compared with pre-treatment 
Grade 2 
Increase in number of stools per 
day (4-6) or nocturnal episodes 
Moderate increase in loose watery colostomy 
output compared with pre-treatment, not 
interfering with normal activity 
Grade 3 
Increase of more than 7 stools per 
day or incontinence or needing 
support for dehydration.   
Severe increase in loose watery colostomy output 
compared with pre-treatment and interfering with 
normal activity 


Clinical Study Protocol Appendix G 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065  
Edition Number 1 
Date 24th January 2013 
7(10)
Table 2 
CTCAE (version 4) grading for diarrhoea 
CTCAE
Grade 
Patients without colostomies 
Patients with colostomies 
Grade 4 
Life-threatening consequences (eg,  hemodynamic collapse) 
3.1 
Initial management of uncomplicated Grade 1 or 2 diarrhoea  

Patients should immediately start loperamide after the first episode of diarrhoea 
(4 mg initially) and continue loperamide (2 mg every 4 hours or after each 
unformed stool) until they have been free from diarrhoea for at least 12 hrs 

If after 12 hours of loperamide treatment the diarrhoea is not improving or resolved, 
the patient should be instructed to contact the centre and to increase to high dose 
loperamide (2 mg every 2 hours, or 4 mg every 4 hours at night) and continue to 
take loperamide until they have been free from diarrhoea for at least 12 hrs.  
Additional treatment may be considered according to local practice. 
3.2 
Management of persistent (>24h) Grade 1 or 2 diarrhoea despite 
loperamide at high dose 
The patient should be seen by the physician or study nurse for full evaluation and the 
following should be considered: 

Rehydration and electrolytes replacement as appropriate 

Infectious causes and aetiologies such as Clostridium difficile or viral 
gastroenteritis; 

Antibiotics if appropriate (for example an oral fluroquinolone for 7 days) 
particularly if the patient is neutropenic (<1 x 109/L) or has a fever; 

Discontinuation of loperamide and start of octreotide (Sandostatin); 
It may also be appropriate to consider: 

Addition of other second-line anti-diarrhoeal agents according to local practice 

Selumetinib (or matching placebo) interruption until resolution of the diarrhoea 

Hospitalisation  
3.3 
Management of any grade uncontrolled or complicated diarrhoea, 
or Grade 3-4 diarrhoea 

Hospitalisation and full evaluation,


Clinical Study Protocol Appendix G 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065  
Edition Number 1 
Date 24th January 2013 
8(10)

Intravenous fluids, electrolytes and antibiotics if needed (eg. fluroquinolone) 

Interrupt selumetinib (or matching placebo) until diarrhoea and associated 
symptoms resolve 

Start octreotide (Sandostatin). 

In studies involving combination of selumetinib (or matching placebo) with other 
anti-cancer treatment, interruption or delay of the combination agent may be 
considered according to manufacturer’s guidance or local practice. 


Clinical Study Protocol Appendix G 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065  
Edition Number 1 
Date 24th January 2013 
9(10)
Figure 1 
Guidance for the management of patients with diarrhoea 
Diarrhoea
CTC Grade 1 or 2
uncomplicated diarrhoea
Loperamide : 4mg initially
then 2mg every 4 hours or
after each unformed stool
Dietary management
Diarrhoea resolving or
resolved after 12hrs of
loperamide treatment
Continue loperamide for 12
hours after diarrhoea
resolved
Adjust diet
Persistent diarrhoea not
resolved after 12 hours of
loperamide and remains 
uncomplicated CTC Grade 1
or 2
Patient should: Contact the
centre and increase to high
dose loperamide (2mg every 2 
hours; possibly 4mg every 4hrs
at night)
Additional treatment may be
considered according to local
practice
Diarrhoea resolving or 
resolved after 24 hours of
high dose loperamide
treatment
Continue loperamide for 12
hours after diarrhoea
resolved 
Adjust diet
Persistent diarrhoea not
resolved after 24 hours of 
high dose loperamide
Full examination.   
Treat as per local practices. 
(Rehydration, electrolytes, 
octreotide, antibiotics, 
hospitalisation). Consider 
selumetinib
‡
dose interruption ** 
CTC Grade 1 or 2
complicated diarrhoea* and 
CTC Grade 3 or 4 at any
time
Hospitalisation 
Treat as per local practices 
(iv rehydration, electrolytes, octreotide, 
iv antibiotics). 
Selumetinib
‡ dose interruption** 
*Diarrhoea becomes complicated by associated vomiting or inability to take oral fluids; marked abdominal 
distension or cramping; bloody stools, fever or symptoms of hypotension 
**Consider interruption or delay of combination anticancer agent if applicable 
‡ selumetinib or matching placebo 
Document version: Final 2.0 28Sept2012 


Clinical Study Protocol Appendix G 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065  
Edition Number 1 
Date 24th January 2013 
10(10)
4. 
RECOMMENDATIONS FOR INVESTIGATIONS OF PATIENTS 
WITH A NEW OR WORSENING DYSPNOEA  
New AE of dyspnoea or 
worsening of pre-existing 
dyspnoea > 1 CTC Grade
The following should be considered based on clinical 
examination:
Chest X-ray, PA and lateral view. Consider Echo, ECG, BNP, 
Troponin I, sputum, blood , urine culture (bacterial antigens and 
PCR), WBC, Hb and urea
If test results indicate diagnosis other 
than ILD/pneumonitis treat according to 
local practices
Consider selumetinib‡ dose interruption 
and/or discontinuation if AE considered 
related to selumumetinib‡ by investigator 
Treatment ineffective
No obvious underlying cause of 
dyspnoea or suspected ILD
Perform HRCT scan
Consider respiratory 
consultation
HRCT does not show 
interstitial lung 
disease/pneumonitis
Dyspnoea AE 
resolved
Continue selumetinib‡
Dyspnoea AE not 
resolved
Seek cardiology and/or 
respiratory consult if not 
already performed. 
Consider selumetinib‡ dose 
interruption/reduction
ILD/pneumonitis
diagnosed by HRCT
Consider selumetinib‡
dose interruption and/or 
discontinuation. 
Treat according to local 
practices
BNP: Brain Natriuretic Peptide
CTC: National Cancer Institute common toxicology criteria
Echo: Echocardiography
Hb: Haemoglobin 
HRCT: High resolution computerised tomography
‡ selumetinib or matching placebo
ILD: Interstitial Lung Disease
PA: posteroanterior 
PCR: Polymerase chain reaction
WBC: White blood cells
Document Version: Final 2.0 28 Sept 2012


33'
33'


 
2(120) 
PROTOCOL SYNOPSIS 
 
A Randomised, Double Blind Study to Compare the Complete Remission 
Rate Following a 5-Week Course of Selumetinib or Placebo and Single Dose 
Adjuvant Radioactive Iodine Therapy in Patients with Differentiated 
Thyroid Cancer 
 
 
International Co-ordinating Investigator  
 
Study centre(s) and number of patients planned 
Approximately 228 patients with newly diagnosed differentiated thyroid cancer at high risk of 
primary treatment failure will be recruited from approximately 50 sites in Europe, South 
and/or North America.     
Objectives 
Primary objective 
To compare the efficacy of selumetinib with radioactive iodine therapy (RAI), versus placebo 
with RAI, by assessment of complete remission rate at 18 months post RAI treatment in the 
intention to treat (ITT) study population. Complete remission is defined in Section 6.4.1. 
Secondary objectives 
To compare the efficacy of selumetinib with RAI, versus placebo with RAI, by assessment of 
complete remission rate at 18 months post RAI treatment in a sub-group of patients with 
tumours known to be mutation positive for BRAF or NRAS (defined in Section 6.10.1). 
Complete remission is defined in Section 6.4.1. 
To compare the efficacy of selumetinib with RAI, versus placebo with RAI by assessment of 
clinical remission rate at 18 months post RAI treatment in the ITT study population. Clinical 
remission is defined in Section 6.4.6. 
To compare the efficacy of selumetinib with RAI, versus placebo with RAI by assessment of 
clinical remission rate at 18 months post RAI treatment in a sub-group of patients with 
tumours known to be mutation positive for BRAF or NRAS (defined in Section 6.10.1). 
Clinical remission is defined in Section 6.4.6. 
To assess the safety and tolerability of selumetinib with RAI compared to placebo with RAI. 
33'


Clinical Study Protocol Synopsis 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
3(120) 
To investigate the pharmacokinetics (PK) of selumetinib and N-desmethyl selumetinib when 
administered to patients with differentiated thyroid cancer. 
Exploratory objectives 
To explore subsequent thyroid cancer therapy given to patients who receive selumetinib with 
RAI, or placebo with RAI. 
To investigate the relationship between selumetinib and/or N-desmethyl selumetinib plasma 
concentrations/exposure and clinical outcomes, efficacy, AEs and/or safety parameters. 
To collect tumour, plasma and serum samples for potential future research on biomarkers 
relevant to DTC and response and resistance to study treatments. 
To collect and store DNA for future exploratory research into genes/genetic variation that may 
influence response (ie, distribution, safety, tolerability and efficacy) to selumetinib or RAI 
and/or susceptibility to cancer. 
Study design 
This is a double-blind, randomised, placebo-controlled study comparing the efficacy of a short 
course (approximately 5 weeks) of selumetinib (75 mg, orally twice daily) with adjuvant RAI, 
to placebo with RAI.  
Following recovery from surgery (1 or 2-stage total thyroidectomy), and screening to 
determine study eligibility, patients will be randomised and will take their assigned study 
treatment (selumetinib or placebo) twice daily for a period of approximately 5 weeks.  Study 
treatment will begin approximately 4 weeks prior to the planned day of single dose RAI 
therapy, and will be continuous until 5 days following RAI therapy.  Patients will be required 
to adhere to a standardised low iodine diet prior to their RAI therapy.  For each of the 2 days 
immediately prior to their planned RAI therapy, patients will receive a 0.9 mg intramuscular 
(IM) recombinant human TSH injection (rhTSH, Thyrogen), in order to stimulate iodide 
uptake (patients or clinicians choosing to prepare for RAI ablation by withdrawal of thyroid 
hormone treatment will be ineligible for this study).  Following the 2 consecutive days of 
rhTSH injections, patients will receive their planned RAI therapy as a fixed single 100 mCi 
(3.7 GBq) dose of 131I the immediate next day. Study treatment will be taken as normal on the 
day of RAI therapy, and will be discontinued 5 days following the patient’s RAI therapy. 
Following RAI therapy, each patient will be followed up for a period of 18 months until the 
primary endpoint assessment of complete remission. The biochemical analysis contributing to 
the 18 month primary endpoint of complete remission will be performed by standardised 
central methodology, and the radiological imaging for structural disease at the primary 
endpoint will be subject to a blinded independent central review. Additional thyroid cancer 
therapy (eg, surgery or RAI treatment) must only be given during the 18 month primary 
endpoint follow up period according to the pre-specified study re-treatment criteria (refer to 
Section 5.9). Patients who do receive re-treatment in the 18 months following their initial RAI 


Clinical Study Protocol Synopsis 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
4(120) 
therapy, will not have any 18 month primary endpoint assessments performed; they will 
remain in the study and enter standard of care follow up according to local practice. 
Following the primary endpoint assessments (or re-treatment), all randomised patients will be 
further followed-up at 3 years after their initial RAI treatment, in order to further assess both 
the clinical status of patients, and the safety profile of selumetinib and RAI beyond the 
primary analysis (refer to Section 6.4.8). 
Target patient population 
Patients with histologically or cytologically confirmed follicular cell derived differentiated 
thyroid cancer (including papillary thyroid cancer and all variants, follicular thyroid cancer 
and all variants, and poorly differentiated thyroid cancer), who are determined to be at high 
risk of primary treatment failure, as defined by any one of the following staging categories 
post-surgery: 
x
Primary tumour greater than 4 cm  
x
Primary tumour of any size with gross extrathyroidal extension outside the thyroid 
gland (T4 disease) 
x
N1a or N1b disease with at least 1 lymph node  1 cm 
x
N1a or N1b disease involving 5 or more lymph nodes (of any size)  
Patients with known distant metastatic disease will be excluded from this study. 
Investigational product, dosage and mode of administration 
Selumetinib Hyd-Sulfate (75 mg) will be administered orally twice daily as capsules (blue).  
The Hyd Sulfate formulation will be used in this study, and unless otherwise specified is the 
formulation referenced throughout this document.  
Comparator, dosage and mode of administration 
Placebo (to match selumetinib) will be administered orally twice daily. 
Duration of treatment 
The duration of study treatment (selumetinib/placebo) will be approximately 5 weeks in total 
(Day 36 will typically be the last day of study treatment, but this may be extended to a 
maximum of 43 days to allow the planned RAI to be postponed by up to 1 week if absolutely 
necessary). 


Clinical Study Protocol Synopsis 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
5(120) 
Outcome variable(s):  
Efficacy 
The primary outcome variable for this study is the rate of complete remission at 18 months 
post-RAI treatment.  Patients will be defined to be in complete remission if all of the 
following criteria can be demonstrated: 
1. 
Serum thyroglobulin (Tg) levels < 1ng/mL during rhTSH stimulation, in the 
absence of interfering Tg antibodies, as assessed by standardised central laboratory 
analysis. 
2. 
No confirmed evidence of thyroid cancera by neck US, as assessed by investigator 
site review. 
3. 
No confirmed radiological evidence of thyroid cancera, as assessed by blinded 
independent central review.  
4. 
No histopathological evidence of thyroid cancer on FNA/biopsy when performed, 
as assessed by investigator site review. 
5. 
No further thyroid cancer therapy was administered in the first 18 months following 
the initial RAI treatment. 
aConfirmation of evidence of structural DTC will be either histopathological (from a 
biopsy/FNA; as criterion 4 above), or RAI-avid disease (refer to Section 6.4.4.2). In this 
disease setting, structural abnormalities that are not RAI-avid and do not have confirmed 
histopathology consistent with DTC (ie are not biopsy proven) are considered benign in the 
absence of biochemical DTC. 
A secondary outcome variable will be the rate of clinical remission at 18 months post-RAI 
treatment, where clinical remission is defined on the basis of Tg, US and WBS assessments 
alone, without the additional radiological data.  
Safety 
AEs/SAEs, physical examination results, lab values, ECG, vital signs. 
All randomised patients will be followed for safety monitoring for 3 years following their RAI 
adjuvant treatment, in order to monitor for selumetinib and RAI-associated side effects. 
PK 
Where sample collection and PK analysis allow, derived PK parameters for selumetinib and  
N-desmethyl selumetinib will be produced which may include, but not be restricted to, Cmax 
and AUC.  Exploratory variables will be analysed outside the clinical study report (CSR). 


Clinical Study Protocol Synopsis 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
6(120) 
Statistical methods 
Approximately 228 patients will be randomised in a 2:1 ratio in this study. The primary 
analysis will be performed when patients have been followed for 18 months following their 
RAI treatment. The primary analysis population will comprise all randomised patients (ITT 
population) and the primary endpoint of complete remission rate at 18 months will be 
analyzed using a logistic regression model including treatment as the only covariate. Results 
will be presented in terms of the odds ratio, 95% confidence interval and associated p-value. 
Logistic regression modelling including treatment and covariates histology status, mutation 
status and age, will be performed as sensitivity analyses provided there are enough data points 
for a meaningful analysis.  
Assuming the true complete remission rates in the ITT study population are 30% and 50% for 
the placebo and selumetinib-containing arms, respectively, the study will have at least 80% 
power to demonstrate a statistically significant difference at the 5% (2-sided) significance 
level.  
All secondary endpoints will be analysed at the time of the primary analysis. Exploratory 
biomarker analysis may be analysed after the time of the primary analysis and reported 
separately to the CSR (apart from the somatic genetic data required for analysis of the second 
primary endpoint). 
All randomised patients will continue to be followed until the final study visit (3 years after 
their RAI treatment). At this time, data on clinical status, incidence of re-treatment and long-
term safety will be summarised. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
7(120) 
TABLE OF CONTENTS 
PAGE
 
TITLE PAGE...........................................................................................................1 
PROTOCOL SYNOPSIS.........................................................................................2 
TABLE OF CONTENTS.........................................................................................7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................14 
1. 
INTRODUCTION .................................................................................................19 
1.1 
Background............................................................................................................19 
1.1.1 
Thyroid Cancer ......................................................................................................19 
1.1.2 
Radioactive iodine treatment .................................................................................19 
1.1.3 
Risk stratified remission rates following RAI treatment .......................................20 
1.1.4 
The benefits of achieving remission ......................................................................22 
1.1.5 
Selumetinib ............................................................................................................23 
1.1.5.1 
MEK and NIS expression ......................................................................................23 
1.1.5.2 
Clinical data in thyroid cancer ...............................................................................25 
1.1.5.3 
Safety profile of selumetinib..................................................................................26 
1.1.5.4 
The pharmacokinetics of Selumetinib in subjects of Asian ethnicity....................30 
1.2 
Research hypothesis...............................................................................................31 
1.3 
Rationale for conducting this study .......................................................................31 
1.4 
Benefit/risk and ethical assessment........................................................................31 
2. 
STUDY OBJECTIVES..........................................................................................32 
2.1 
Primary objective...................................................................................................32 
2.2 
Secondary objectives .............................................................................................32 
2.3 
Exploratory objectives ...........................................................................................33 
3. 
STUDY PLAN AND PROCEDURES ..................................................................33 
3.1 
Overall study design and flow chart ......................................................................33 
3.1.1 
Treatment Plan.......................................................................................................34 
3.1.2 
Follow-up plan.......................................................................................................35 
3.2 
Rationale for study design, doses and control group .............................................45 
4. 
PATIENT SELECTION CRITERIA.....................................................................47 
4.1 
Inclusion criteria ....................................................................................................47 
4.1.1 
Genetics research study (optional blood sample) ..................................................50 
4.1.2 
Biomarkers research study on tumour progression biopsy....................................50 
4.2 
Exclusion criteria ...................................................................................................50 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
8(120) 
4.2.1 
Genetics research study (optional blood sample) ..................................................52 
5. 
STUDY CONDUCT..............................................................................................53 
5.1 
Restrictions during the study .................................................................................53 
5.1.1 
Low-iodine diet......................................................................................................53 
5.1.2 
Other study restrictions..........................................................................................53 
5.2 
Patient enrolment, randomisation and initiation of investigational product..........54 
5.2.1 
Procedures for randomisation ................................................................................55 
5.3 
Procedures for handling patients incorrectly enrolled, randomised or 
initiated on investigational product........................................................................55 
5.4 
Blinding and procedures for unblinding the study.................................................55 
5.4.1 
Methods for ensuring blinding...............................................................................55 
5.4.2 
Methods for unblinding the study..........................................................................56 
5.5 
Treatments..............................................................................................................56 
5.5.1 
Identity of investigational product(s).....................................................................56 
5.5.2 
Doses and treatment regimens ...............................................................................56 
5.5.3 
Management of study treatment related toxicity ...................................................57 
5.5.3.1 
Selumetinib dose interruption or reduction............................................................57 
5.5.3.2 
Management and investigation of specific selumetinib related AEs.....................58 
5.5.4 
Additional study drugs...........................................................................................59 
5.5.4.1 
Thyrogen (rhTSH, thyrotropin alfa for injection)..................................................59 
5.5.4.2 
Radioactive iodine (RAI).......................................................................................59 
5.5.4.3 
Thyroid hormone supplementation (TSH suppression).........................................60 
5.5.5 
Study drug labelling...............................................................................................60 
5.5.6 
Storage ...................................................................................................................60 
5.6 
Concomitant medications.......................................................................................60 
5.7 
Treatment compliance............................................................................................61 
5.7.1 
Accountability........................................................................................................61 
5.8 
Discontinuation of investigational product............................................................62 
5.8.1 
Procedures for premature discontinuation of a patient from investigational 
product ...................................................................................................................62 
5.9 
Criteria for further thyroid cancer therapy during the study..................................63 
5.9.1 
Re-treatment prior to the 18 month primary endpoint assessments.......................63 
5.9.1.1 
Biochemical disease re-treatment criteria..............................................................63 
5.9.1.2 
Structural disease re-treatment criteria ..................................................................64 
5.9.1.3 
Patient management on study (up to the primary analysis at 18 months 
post-RAI) ...............................................................................................................64 
5.9.2 
Re-treatment after the 18 month primary endpoint assessments ...........................65 
5.10 
Withdrawal from study ..........................................................................................65 
5.11 
Replacement of patients.........................................................................................65 
6. 
COLLECTION OF STUDY VARIABLES...........................................................66 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
9(120) 
6.1 
Recording of data...................................................................................................66 
6.2 
Data collection at enrolment ..................................................................................66 
6.2.1 
Performance status definitions...............................................................................67 
6.3 
Post-operative imaging assessments for eligibility................................................67 
6.4 
Efficacy..................................................................................................................68 
6.4.1 
Complete remission ...............................................................................................68 
6.4.2 
Staged approach to primary endpoint assessments................................................69 
6.4.2.1 
Primary endpoint assessments Stage 1 ..................................................................72 
6.4.2.2 
Primary endpoint assessments Stage 2 ..................................................................73 
6.4.2.3 
Primary endpoint assessments Stage 3 ..................................................................76 
6.4.3 
Blood sample assessments for efficacy..................................................................76 
6.4.3.1 
Suppressed Tg........................................................................................................76 
6.4.3.2 
Stimulated Tg.........................................................................................................77 
6.4.3.3 
TSH........................................................................................................................77 
6.4.3.4 
Tg antibody (TgAb) ...............................................................................................78 
6.4.4 
Imaging assessments for efficacy ..........................................................................79 
6.4.4.1 
Neck ultrasound (US) ............................................................................................79 
6.4.4.2 
Whole body diagnostic 131I nuclear medicine scan (WBS) ...................................80 
6.4.4.3 
Neck MRI...............................................................................................................81 
6.4.4.4 
Chest CT ................................................................................................................82 
6.4.4.5 
Biopsy or fine needle aspirate (FNA) ....................................................................82 
6.4.4.6 
Information to be sent to the central imaging CRO...............................................83 
6.4.5 
Derivation of primary endpoint of complete remission.........................................84 
6.4.6 
Clinical remission ..................................................................................................86 
6.4.7 
Derivation of clinical remission status...................................................................86 
6.4.8 
Final study follow up at 3 years.............................................................................87 
6.5 
Safety .....................................................................................................................87 
6.5.1 
Definition of adverse events ..................................................................................87 
6.5.2 
Definitions of serious adverse event......................................................................88 
6.5.3 
Recording of adverse events ..................................................................................88 
6.5.3.1 
Disease progression ...............................................................................................91 
6.5.4 
Reporting of serious adverse events.......................................................................91 
6.5.5 
Laboratory safety assessment ................................................................................92 
6.5.6 
Physical examination .............................................................................................93 
6.5.7 
Cardiac monitoring ................................................................................................93 
6.5.7.1 
ECHO or MUGA ...................................................................................................93 
6.5.7.2 
Resting 12-lead ECG .............................................................................................93 
6.5.8 
Vital signs ..............................................................................................................94 
6.5.9 
Other safety assessments........................................................................................94 
6.5.9.1 
Pregnancy test ........................................................................................................94 
6.5.9.2 
Ophthalmologic examination.................................................................................94 
6.6 
Patient reported outcomes (PRO) – not applicable................................................94 
6.7 
Pharmacokinetics ...................................................................................................95 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
10(120) 
6.7.1 
PK samples required ..............................................................................................95 
6.7.2 
Determination of drug concentration.....................................................................95 
6.8 
Pharmacodynamics – not applicable......................................................................95 
6.9 
Pharmacogenetics ..................................................................................................96 
6.9.1 
Genetic blood sample at study entry......................................................................96 
6.10 
Biomarker analysis.................................................................................................96 
6.10.1 
BRAF and NRAS patient population ......................................................................96 
6.10.1.1 Archival tumour sample.........................................................................................96 
6.10.2 
Collection of plasma and serum for exploratory biomarker research....................97 
6.10.3 
Collection of disease progression tumour sample..................................................98 
7. 
BIOLOGICAL SAMPLING PROCEDURES.......................................................99 
7.1 
Volume of blood ....................................................................................................99 
7.2 
Handling, storage and destruction of biological samples ....................................100 
7.2.1 
Pharmacokinetic samples.....................................................................................100 
7.2.2 
Pharmacogenetic samples ....................................................................................100 
7.3 
Labelling and shipment of biohazard samples.....................................................101 
7.4 
Chain of custody of biological samples...............................................................101 
7.5 
Withdrawal of informed consent for donated biological samples .......................101 
8. 
ETHICAL AND REGULATORY REQUIREMENTS.......................................102 
8.1 
Ethical conduct of the study.................................................................................102 
8.2 
Patient data protection..........................................................................................102 
8.3 
Ethics and regulatory review................................................................................102 
8.4 
Informed consent .................................................................................................103 
8.5 
Changes to the protocol and informed consent form...........................................104 
8.6 
Audits and inspections .........................................................................................104 
9. 
STUDY MANAGEMENT BY ASTRAZENECA..............................................104 
9.1 
Pre-study activities...............................................................................................104 
9.2 
Training of study site personnel...........................................................................105 
9.3 
Monitoring of the study .......................................................................................105 
9.3.1 
Source data...........................................................................................................105 
9.4 
Study agreements.................................................................................................106 
9.4.1 
Archiving of study documents.............................................................................106 
9.5 
Study timetable and end of study.........................................................................106 
10. 
DATA MANAGEMENT BY ASTRAZENECA OR DELEGATE....................106 


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Drug Substance Selumetinib (AZD6244)  
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11. 
EVALUATION AND CALCULATION OF VARIABLES BY 
ASTRAZENECA OR DELEGATE ....................................................................107 
11.1 
Calculation or derivation of efficacy variable(s) .................................................107 
11.1.1 
Complete remission rate at 18 months post-RAI treatment.................................107 
11.1.2 
Clinical remission rate at 18 months post-RAI treatment....................................107 
11.1.3 
Thyroid cancer recurrence ...................................................................................107 
11.1.4 
Survival status......................................................................................................108 
11.1.5 
Further therapy.....................................................................................................108 
11.2 
Calculation or derivation of safety variable(s).....................................................108 
11.2.1 
Adverse events.....................................................................................................108 
11.2.2 
Other significant adverse events (OAE) ..............................................................108 
11.2.3 
Vital signs, laboratory data, ECGs, ECHO/MUGA, physical examination 
and ophthalmologic examination.........................................................................109 
11.3 
Calculation or derivation of PK variables............................................................109 
11.4 
Calculation or derivation of pharmacogenetic variables......................................109 
11.5 
Calculation or derivation of biomarker variables ................................................110 
11.5.1 
Analysis of NRAS and BRAF ...............................................................................110 
11.5.2 
Further biomarker research analysis ....................................................................110 
12. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION..........110 
12.1 
Description of analysis sets..................................................................................110 
12.1.1 
Intention to treat (ITT) analysis set......................................................................110 
12.1.2 
BRAF/NRAS mutation positive analysis set.........................................................110 
12.1.3 
Treatment-compliant (TC) analysis set................................................................110 
12.1.4 
Safety analysis set................................................................................................110 
12.1.5 
PK analysis set .....................................................................................................111 
12.2 
Methods of statistical analyses.............................................................................111 
12.2.1 
Complete remission rate at 18 months post-RAI treatment.................................111 
12.2.2 
Clinical remission rate at 18 months post-RAI treatment....................................113 
12.2.3 
Thyroid cancer recurrence ...................................................................................113 
12.2.4 
Survival status......................................................................................................113 
12.2.5 
Further therapy.....................................................................................................113 
12.2.6 
Safety data analysis..............................................................................................113 
12.2.7 
PK data analysis...................................................................................................113 
12.2.8 
Genetics................................................................................................................113 
12.2.9 
Biomarker data.....................................................................................................114 
12.2.10 
Interim analyses ...................................................................................................114 
12.3 
Determination of sample size...............................................................................114 
12.4 
Data monitoring committee .................................................................................114 
13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR ................................................................................................115 


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13.1 
Medical emergencies and AstraZeneca contacts .................................................115 
13.2 
Overdose ..............................................................................................................115 
13.3 
Pregnancy.............................................................................................................116 
13.3.1 
Maternal exposure................................................................................................116 
13.3.2 
Paternal exposure.................................................................................................116 
14. 
LIST OF REFERENCES.....................................................................................117 
 
LIST OF TABLES 
Table 1 
Remission rates in 2 independent data sets of risk-categorised 
patients with differentiated thyroid cancer - based on tumour size 
and lymph node status ..............................................................................21 
Table 2 
Example study treatment plan ..................................................................35 
Table 3 
Study Plan.................................................................................................38 
Table 4 
Study Plan for the 18 month Primary Endpoint Assessments..................43 
Table 5 
Criteria for biochemical decision making (based on standardised 
central analysis results).............................................................................75 
Table 6 
Programmatic derivation of complete remission status............................85 
Table 7 
Laboratory safety assessments .................................................................92 
Table 8 
Biomarker summary table ........................................................................99 
Table 9 
Volume of blood to be drawn from each patient......................................99 
 
LIST OF FIGURES 
Figure 1 
Study flow chart .......................................................................................37 
Figure 2 
Time course to achieving a suppressed Tg<1 ng/mL in patients 
receiving total thyroidectomy and RAI therapy .......................................46 
Figure 3 
Flow chart for staged primary endpoint assessments...............................71 
 
LIST OF APPENDICES 
 
Appendix A  
Signatures 
Appendix B  
Additional Safety Information 


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Appendix C  
IATA 6.2 Guidance document 
Appendix D  
Actions Required in Cases of Combined Increase of Aminotransferase and 
Total Bilirubin – Hy’s Law 
Appendix E  
Cockcroft-Gault Formula 
Appendix F 
Low Iodine Diet 
Appendix G  
Guidance for Management of Adverse Events in Studies of Selumetinib 


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Edition Number 4 
Date 01 July 2014 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
124I 
Iodine-124 
131I 
Iodine-131 (radioactive iodine; RAI) 
AE 
Adverse event (see definition in Section 6.5.1) 
AJCC 
American Joint Committee on Cancer 
ALP 
Alkaline phosphatise 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
ATA 
American Thyroid Association 
ATC 
Anaplastic thyroid cancer 
AUC 
Area under the plasma concentration-time curve from zero to infinity 
BD 
Twice daily (dosing) 
bid 
bis in die – twice a day 
BNP 
B-type natriuretic peptide 
BP 
Blood pressure 
Bpm 
Beats per minute 
BRAF 
v-raf murine sarcoma viral oncogene homolog B1 
cm 
centimetres 
Cmax 
Maximum plasma concentration 
CRF 
Case report form (electronic/paper) 
CR 
Clinical remission 
CR 
Complete remission 
CSA 
Clinical study agreement 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse event 
DAE 
Discontinuation of investigational product due to adverse event 
DNA 
Deoxyribonucleic acid  
DTC 
Differentiated thyroid cancer 
D-TC-FCO 
Differentiated thyroid carcinoma of follicular cell origin 


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Edition Number 4 
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Abbreviation or 
special term 
Explanation 
DUS 
Disease under study 
EBRT 
External beam radiation therapy 
EC 
Ethics committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
ERK 
Extracellular signal-regulated kinases 
ETA 
European Thyroid Association 
FDG-PET 
2-[F-18]-fluoro-2-deoxy-D-glucose positron emission tomography 
FNA 
Fine needle aspiration 
FSH 
Follicle stimulating hormone 
FTC 
Follicular thyroid cancer 
G1 
Gap 1 phase of the cell cycle 
GCP 
Good clinical practice 
g/dL 
grams per decilitre 
GMP 
Good manufacturing practice 
hr 
hour 
I 
Iodine 
IATA 
International Air Transport Association 
IB 
Investigator brochure 
ICH 
International Conference on Harmonisation 
ICH M3 
The European Medicines Agency’s International Conference on Harmonisation 
Topic M3 – “Non-Clinical Safety Studies for the Conduct of Human Clinical Trials 
and Marketing Authorization for Pharmaceuticals” 
IM 
Intramuscular 
INR 
International normalised ratio 
International 
Co-ordinating investigator 
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or activities 
internationally.  
IP 
Investigational product  
ITT 
Intention-to-treat 
IUD 
Intrauterine device 
IV 
Intravascular 
IVRS 
Interactive voice response system 


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Abbreviation or 
special term 
Explanation 
IWRS 
Interactive web response system 
kg 
kilograms 
KRAS 
v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 
LH 
Luteinizing hormone 
LIMS 
Laboratory information management system 
LLOQ 
Lower limit of quantification 
LSLV 
Last patient last visit 
LT4 
Synthetic levothyroxine 
LV 
Left ventricular 
LVEF 
Left ventricular ejection fraction 
M0, M1, Mx  
Distant metastasis status (TNM cancer staging system) 
MAPK 
Mitogen-activated protein kinase 
mCi 
millicuries 
MedDRA 
Medical dictionary for regulatory activities 
MEK 
MAPK/ERK kinase 
MI 
Myocardial infarction 
Pg/L 
micrograms per litre 
Pm 
micrometers 
mIU/L 
milli-International units per litre 
mg 
milligrams 
mg/day 
milligrams per day 
mL 
millilitres 
mL/min 
millilitres per minute 
mm 
millimetres 
mm3 
cubic millimetres 
ms 
milliseconds 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
MSKCC 
Memorial Sloan Kettering Cancer Center 
MTD 
Maximum tolerated dose 
MUGA 
Multi-gated acquisition scan 
N0, N1, Nx etc 
Lymph node disease stage (TNM cancer staging system) 
N/A 
Not applicable 
ng/mL 
nanograms per milliliter 


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Edition Number 4 
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Abbreviation or 
special term 
Explanation 
NIS 
Sodium iodide symporter 
NOEL 
No observed effect level 
NSCLC 
Non-small cell lung cancer 
NTRK 
Neurotrophic tyrosine kinase, receptor, type 1 
NYHA 
New York Heart Association 
OAE 
Other significant adverse event (see definition in Section 6.5) 
PDTC 
Poorly differentiated thyroid carcinomas 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PGx 
Pharmacogenetic research 
PI 
Principal investigator  
PK 
Pharmacokinetics 
PRO 
Patient reported outcomes 
PTC 
Papillary thyroid cancer 
RAI 
Radioactive iodine (131I) 
RET 
Ret proto-oncogene 
Rb 
Retinoblastoma protein 
RECIST 
Response Evaluation Criteria In Solid Tumours 
rhTSH 
Recombinant human thyroid stimulating hormone 
SAE 
Serious adverse event (see definition in Section 6.5.2). 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis software 
SBE-CD 
Sulphobutylether ȕ-cyclodextrin 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
SUV 
Standard uptake value 
T0, T1, Tx etc 
Primary tumour disease stage (TNM cancer staging system) 
T4 
Free thyroxine 
Tg 
Thyroglobulin 
TgAb 
Thyroglobulin antibody 
TNM 
Tumour, nodes, metastasis cancer staging system 
TPGS 
D-Į tocopheryl polyethylene glycol 1000 succinate 


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Edition Number 4 
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Abbreviation or 
special term 
Explanation 
TPO 
Thyroid peroxidase 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
US 
Ultrasound 
WBDC 
Web based data capture 
WBS 
Whole body scintigraphy (also whole body scan) 
WHO 
World Health Organisation 
Wk 
Week 
 


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1. 
INTRODUCTION 
1.1 
Background 
1.1.1 
Thyroid Cancer 
There are approximately 56,500 new cases of thyroid cancer diagnosed in the USA per year, 
and approximately 34,000 new cases diagnosed in Europe per year.  Thyroid cancers are 
classified according to their histopathological characteristics into 4 main variants: papillary 
thyroid cancer (PTC, the most common), follicular thyroid cancer,  medullary thyroid cancer 
and anaplastic (undifferentiated) thyroid cancer.  The papillary and follicular types together 
can be classified as differentiated thyroid cancer (DTC), and make up approximately 95% of 
thyroid cancers. All DTC (including PTC) begins in the follicular cells of the thyroid gland 
and is termed “of follicular cell origin.”  Other, rarer variants of thyroid cancer of follicular 
cell origin include Hürthle cell carcinoma and poorly differentiated thyroid cancer (PDTC). 
DTC is generally indolent and has a natural history which is measured in decades if treated 
appropriately (up to 95% 10 year survival). However there are very limited options for 
patients who ultimately fail radioactive iodine therapy and develop distant refractory 
metastases, and most of these patients will succumb to their disease (Durante et al 2006).  
1.1.2 
Radioactive iodine treatment  
In addition to primary thyroid surgery, radioactive iodine (RAI, 131I) is the mainstay of 
therapy for patients with thyroid cancer of follicular origin. It is a targeted therapeutic 
approach that exploits the expression of the sodium iodide symporter (NIS) to deliver 
radiation selectively to thyroid cells, which is used as adjuvant therapy after thyroidectomy, 
and to treat recurrent and metastatic disease.   
Most patients with thyroid cancer of follicular origin have differentiated carcinomas which 
retain at least to some extent the biological properties of normal thyroid cells, including 
expression of NIS. Presence of this transporter is required for iodine uptake (Riesco-
Eizaguirre et al 2006). 
Following diagnosis, surgical resection of the thyroid gland with or without removal of the 
local lymph nodes is performed. Following surgical resection, a set of clinical-pathologic data 
(such as age at diagnosis, specific histological type, size of the primary tumour, extent of 
lymph node metastases, presence of distant metastases, gross extrathyroidal extension and 
completeness of resection) can be used to estimate the risk of recurrence and the risk of 
disease specific mortality. After surgery, radioactive iodine can be used for the following 
purposes: 
For diagnostic scanning to improve initial staging and extent of disease assessment. 
For ablation of the normal thyroid remnant (usually less than 2-3% of normal tissue remains 
after total thyroidectomy). This treatment facilitates follow-up by achieving an undetectable 
level of serum thyroglobulin and a subsequent negative diagnostic whole body RAI scan. 


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As adjuvant therapy, in an attempt to destroy microscopic residual disease in patients at 
intermediate to high risk of recurrence. 
As primary therapy in patients with unresectable RAI-avid loco-regional disease or distant 
metastases.   
Uptake of RAI by tumour tissue is a prerequisite for administration of RAI treatment and for 
its efficacy. Once patients develop distant metastatic disease, RAI uptake is observed in only 
two thirds of cases and less frequently in patients with aggressive disease (Durante et al 2006, 
Mazzaferri and Kloos 2001, Nemec et al 1979, Samaan et al 1985).  Patients with no uptake in 
metastatic foci are considered refractory to RAI, which is then no longer indicated. 
1.1.3 
Risk stratified remission rates following RAI treatment 
Several different risk stratification systems have been published for DTC.  The Union 
Internationale Contre le Cancer/American Joint Committee on Cancer (AJCC) staging system 
is the most commonly used, but it was developed to predict the risk of death rather than 
recurrence.  To overcome this limitation, the American Thyroid Association (ATA) published 
guidelines to grade the risk of recurrence into 3 categories (low, intermediate, and high) based 
on tumour-related parameters (pathological tumour-node-metastasis and histological variant) 
integrated with other clinical features, including the result of the first post-therapy RAI whole-
body scan and serum Tg measurement.  Although the ATA risk stratification system has been 
shown to better predict short-term clinically relevant endpoints of persistent and recurrent 
disease than the AJCC system, it does not adequately predict longer-term outcomes because 
the risk of persistent or recurrent disease changes following initial therapy. In addition, the 
ATA intermediate risk category includes a wide variety of potential risk factors that can have 
a significant influence on both short term and long-term outcomes (any tumour size, N1a/N1b 
node status, vascular invasion, extrathyroidal extension, aggressive histology).  
Recent evidence suggests that the likelihood of achieving remission varies depending on the 
size of the primary tumour, extent of invasion, or lymph node status as defined by number and 
size of affected nodes (refer to Table 1, Tuttle, unpublished sub-analysis of data from Tuttle et 
al 2010 and Vaisman et al 2012). 


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Table 1 
Remission rates in 2 independent data sets of risk-categorised patients 
with differentiated thyroid cancer - based on tumour size and lymph 
node status 
TNM 
status 
Description 
Remission ratea 
MSKCCb 
n=588 patients 
Remission ratea 
Brazilc 
n=506 patients 
T1 
Tumour diameter 2 cm or smaller 
40% 
59% 
T2 
Tumour diameter 2 - 4 cm 
47% 
52% 
T3 
Tumour diameter > 4 cm or with minimal extrathyroidal 
extension 
25% 
37% 
T4 
Tumour of any size extending to invade subcutaneous soft 
tissues, larynx, trachea, esophagus, recurrent laryngeal 
nerve, prevertebral fascia or encasing carotid artery or 
mediastinal vessels 
13% 
17% 
N0 
No metastatic nodes identified 
62% 
54% 
N1a 
Metastatic nodes in central neck (pretracheal, 
paratracheal, or prelaryngeal) 
31% 
30% 
N1b 
Metastatic nodes in lateral neck or superior mediastinum 
16% 
12% 
a Remission rate within a 2 year follow up period 
b unpublished sub-analysis of data from Tuttle et al 2010 
c unpublished sub-analysis of data from Vaisman et al 2012 
As can be seen patients with either T3 disease or N1a disease have remission rates that 
approximate 30%, while patients with T4 disease or N1b disease have remission rates that 
approximate 15%.  From a clinical perspective, these findings are not surprising since T3 
disease is very commonly associated with N1a disease, and T4 disease is often associated with 
N1b disease.  Therefore, the similarity in remission rates in T3 and N1a disease, and in T4 and 
N1b disease, is consistent with observations in clinical practice.   
It is important to note that in addition to the location of the lymph node metastases (N1a vs. 
N1b), the extent of lymph node metastases (size and number of involved nodes) is also a 
critical factor in assessing the risk of recurrence and risk of failing initial therapy (Randolph et 
al, 2012, Ricarte-Filho et al 2012). The complete remission rates from the MSKCC and 
Brazilian cohorts are based on patients with clinically significant, structurally evident N1a 
and/or N1b disease that required therapeutic neck dissections for clinically apparent metastatic 
disease (prophylactic neck dissections to remove sub-clinical disease were not performed in 
either the MSKCC or Brazilian cohorts).  For example, in a MSKCC series of 246 papillary 
thyroid cancer patients who presented with lymph node metastases at the time of diagnosis, a 
median of 6 metastatic lymph nodes were identified with a median maximal diameter of 1.3 
cm (Ricarte-Filho et al 2012).  Furthermore, multiple studies have demonstrated that small 
volume lymph node metastases which are usually identified as incidental findings in the 
fibroadipose tissue surrounding the thyroid, or as a result of prophylactic central neck 
dissections, are associated with a low risk of recurrence (Randolph et al, 2012, Ricarte-Filho 
et al 2012), and these may not even require RAI adjuvant therapy (and therefore would not be 


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appropriate subjects for the proposed study).  Therefore, to prevent patients with lower risk 
N1a or N1b small volume metastatic disease from enrolling into this study, a requirement is 
that subjects must have N1a or N1b disease involving 5 or more lymph nodes (of any size) or 
at least 1 lymph node  1 cm in the largest diameter. 
Since only approximately 30% of patients presenting with any of the following features are 
expected to achieve clinical remission following total thyroidectomy and RAI remnant 
ablation, they are at high risk of failing their primary treatment: 
x
Primary tumour greater than 4 cm 
x
Primary tumours of any size with gross extrathyroidal extension outside the thyroid 
gland (T4 disease) 
x
N1a or N1b disease with at least 1 lymph node  1 cm 
x
N1a or N1b disease involving 5 or more lymph nodes (of any size) 
Total thyroidectomy and RAI ablation is therefore very effective at inducing remission in low 
risk patients, however approximately 70% of patients with the above characteristics do not 
enter remission, and have an incomplete response to initial therapy with biochemical and/or 
structural evidence of persistent disease. 
1.1.4 
The benefits of achieving remission 
Thyroid cancer deaths are exceedingly rare if remission is achieved, and studies have shown 
that nearly all deaths ultimately occur in the group of patients who do not achieve remission. 
For example, two recent studies reported disease-specific deaths in 6% and 8% of the patients 
who did not achieve remission compared to 0% in patients who achieved remission with 
median follow-up times of 7 and 10 years respectively (Tuttle RM, unpublished sub-analysis 
of data from Tuttle et al 2010, Vaisman et al 2012).  This mortality rate continues to rise with 
longer periods of follow up with nearly all deaths from thyroid cancer being seen in the cohort 
of patients that failed to achieve remission.   
The importance of a successful initial therapy is demonstrated by the excellent prognosis that 
even high-risk patients have if therapy results in negative imaging and negative thyroglobulin 
levels after stimulation by TSH. The majority of patients who achieve remission do not 
relapse; recurrence rates are typically 1% to 4% over median follow-up periods of 5 to 10 
years for patients who achieve remission (Castagna et al 2011, Tuttle et al 2010, Vaisman et al 
2012).     
In patients that achieve remission, there are important clinical and psychological benefits. 
Patients that achieve remission are re-classified as low risk patients and require much less 
frequent follow-up. Thyroglobulin testing and imaging assessments are reduced in frequency, 
and less aggressive TSH suppressive therapy is required. This in turn reduces the longer-term 
risks of osteoporosis and atrial fibrillation that are known complications of supra-


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physiological dosing of levothyroxine, and reduces the anxiousness and fatigue that can result 
from the mildly hyperthyroid state caused by TSH suppression. 
If remission is not achieved with initial therapy, many patients will be subjected to additional 
therapies (eg, more RAI, surgery, external beam irradiation), in an effort to control disease 
progression and achieve a cure.  Therapeutic RAI is associated with a cumulative dose-related 
risk of early and late-onset complications such as salivary gland damage, dental caries, 
nasolacrimal duct obstruction, and decreased fertility (Cooper et al 2009). Furthermore, a 
dose-dependent relationship is also seen between cumulative administered RAI activity and 
the subsequent occurrence of secondary malignancies (Rubino et al 2003, Sawka et al 2009). 
All of these risks and symptoms constitute significant quality of life issues for the patient. The 
inconvenience of repeating a low iodine diet, the associated radiation safety precautions and 
missed days of work are additional factors the patient must consider.  Additional surgery 
carries associated risks related to anesthesia, nerve damage (resulting in hoarseness, 
permanent tracheotomy in rare occasions, drooping eye lid, loss of control of shoulder 
muscles and loss of sensation in the neck), increased scarring in the neck (resulting in 
discomfort and difficulty swallowing), and damage to the parathyroid glands (resulting in 
hypocalcemia and a lifetime need for vitamin D and calcium supplementation and frequent 
blood tests). Thus avoidance of further therapy is beneficial to the patient. 
Unfortunately, additional therapy is often less effective, particularly in patients with persistent 
structural disease (Vaisman et al, 2011). Further RAI can be given to patients that have 
persistent biochemical evidence of disease, and although repeat RAI is often less effective 
than the initial RAI treatment (especially for patients with persistent structural disease), it can 
be effective at driving some patients with persistent biochemical disease into remission. Thus, 
strategies designed to improve the tumouricidal effect of the initial RAI dose should result in 
higher remission and cure rates. 
An intervention that enhances the effectiveness of initial therapeutic RAI in higher risk 
patients (the target population for this study), should result in higher remission rates and 
remove the need for further therapy, and would thus be of clear benefit to patients. 
1.1.5 
Selumetinib 
Selumetinib is a potent, selective, noncompetitive inhibitor of MEK, licensed for development 
by AstraZeneca Pharmaceuticals from Array BioPharma.  Selumetinib was discovered by 
Array Biopharma and had the designation ARRY 142886.  Other laboratory code names used 
during the development of this molecule are AR00142886 and AR-142886-X (where X refers 
to a sequential lot number).  Array BioPharma was responsible for the first-into-human study; 
the remainder of the clinical development programme for oncology indications is the 
responsibility of AstraZeneca.  AZD6244 has now been assigned the international non-
proprietary name selumetinib.   
1.1.5.1 
MEK and NIS expression  
Papillary thyroid cancer (PTC), which is the most common form of the disease, is 
characterised by a set of genetic alterations, all of which result in the activation of 


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RAF/MEK/ERK signalling. Of these genetic lesions the most common is the typical V600E 
mutant of BRAF also found in other cancers, most notably melanoma. The other genetic 
lesions occur in receptor tyrosine kinases (RET and NTRK1), and in RAS (N and HRAS). In 
total these mutations in effectors of ERK signalling account for approximately 70% of 
papillary thyroid cancer (Kimura et al 2003, Soares et al 2003). BRAF itself is seen in at least 
38% of PTC, and is also found in poorly differentiated and anaplastic thyroid carcinomas with 
a prevalence of 12% and 50%, respectively (Nikiforova et al 2003, Ricarte-Filho et al 2009). 
These genetic mutations are mutually exclusive and suggest the importance of 
RAF/MEK/ERK signalling in papillary thyroid cancer.  
With regard to the impact on efficacy of RAI therapy, one of the primary effects of activation 
of the RAF/MEK/ERK signalling pathway is a significant and sustained down regulation of 
the sodium iodide symporter (NIS) which is responsible for the uptake of iodine into thyroid 
cells and is required for the uptake of therapeutic 131I into thyroid cancer cells. Studies have 
demonstrated that the expression of NIS (and other genes typical of differentiated thyroid 
cells) is suppressed by activation of RAF/MEK/ERK signalling in mouse models of the 
disease (Franco A et al. 2011). In mice engineered to express V600E BRAF in thyroid cells, 
expression of NIS and other thyroid differentiation markers is reduced (Knauf et al 2005). 
These mice develop papillary thyroid cancers with dedifferentiated features. Further data 
using a mouse model of thyroid-specific inducible expression of V600E BRAF, show that 
V600E BRAF activation suppresses expression of NIS, thyroid peroxidase (TPO) and 
thyroglobulin (Tg), and blocks 124I uptake, all of which are re-established once expression of 
oncogenic BRAF is turned off. Treatment of mice expressing the induced V600E BRAF with a 
MEK inhibitor also re-established NIS expression and 124I uptake in the poorly differentiated 
thyroid carcinomas (PDTC) (Chakravarty D et al 2011). Constitutive activation of MAPK 
signalling also inhibits the expression of thyroid peroxidase and thyroglobulin in BRAF-
induced murine thyroid cancers. Genetic or pharmacological blockade of the pathway restores 
their expression, and consequently the ability to incorporate iodine into tyrosine (iodine 
organification), which is associated with greater retention time of 131I in cancer cells 
(Chakravarty D et al 2011). Other MAPK activating alterations common to thyroid cancer can 
also cause de-differentiation.  Over-expression of either the G12V HRAS mutant or RET/PTC 
in thyroid cancer cells suppresses NIS, thyroglobulin and thyroid peroxidase expression, 
which is restored with MEK inhibitor treatment (Knauf et al 2003, De Vita et al, 2005).  These 
experiments provide a pre-clinical proof of concept that inhibition of ERK signalling by MEK 
inhibitors can reverse the suppression of NIS, TG and TPO expression and re-establish iodine 
incorporation into PTC. 
NIS expression in clinical thyroid cancer samples 
Analysis of clinical tumour samples for NIS expression indicates a relative loss of NIS 
expression (and the expression of other thyroid specific genes) relative to normal thyroid 
tissue (Durante et al 2007; Espadinha et al 2009). Furthermore, NIS expression is lower in 
BRAF mutant tumours than in those without BRAF mutation (Durante et al 2007; Morai et al 
2011; Romei et al 2008).  In a well differentiated rat thyroid cell line model, expression of 
RET/PTC, mutant HRAS, or constitutively active MEK1, blocked TSH-induced expression of 
Tg and NIS; an effect that was reversed by MEK inhibition.  These data are consistent with 


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Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
25(120) 
the hypothesis that activation of MEK, regardless of the upstream activating mutation is a key 
factor in the loss of thyroid differentiation specific gene expression including NIS (Knauf et al 
2003). 
In summary, this data predicts that both an unselected and genetically selected population may 
benefit from treatment with a MEK inhibitor and RAI. This study will thus assess two 
populations for the primary endpoint of complete remission rate at 18 months; the genetic ‘all 
comer’ population, and also a population of patients with tumours carrying BRAF or NRAS 
mutations, as these are known to constitutively activate the MEK signalling pathway. 
Treatment with a MEK inhibitor may thus be hypothesised to deliver a greater treatment effect 
in these patients. However, the pathway can be activated in many ways such that other 
patients may also benefit.  
1.1.5.2 
Clinical data in thyroid cancer 
The preclinical data generated to date suggests the clinical hypothesis that MAPK pathway 
inhibition in patients with RAI-refractory tumours will result in reacquisition of RAI uptake 
and renewed susceptibility to therapeutic 131I.  To test this hypothesis, an investigator-
sponsored selumetinib pilot study has been performed at MSKCC for patients with RAI-
refractory recurrent or metastatic differentiated thyroid carcinoma of follicular cell origin 
entitled, “Reacquisition Of RAI Uptake Of RAI-Refractory Metastatic Thyroid Cancers By 
Pre-treatment With The Selective MEK Inhibitor Selumetinib: A Pilot Study” (Ho et al 2012).  
In this study, the RAI avidity of thyroid tumours was quantified by lesional dosimetry with 
124I PET imaging in patients, before and after 4 weeks of treatment with selumetinib.  For 
patients whose tumours reacquired the ability to take up RAI, 131I treatment was administered, 
and tumour response was assessed both radiographically and with measurement of the serum 
tumour marker thyroglobulin (Tg).   
20 patients were treated with selumetinib in this pilot study.  Of the 20 patients, 9 patients had 
tumours with the V600E BRAF mutation, 5 patients had tumours with NRAS mutations at 
codon 61, 3 patients had tumours with RET/PTC rearrangements, and the remaining 3 patients 
were wild-type for these alterations. Twelve of the 20 patients in the study demonstrated 
increased tumoural 124I uptake, and 8 of these 12 patients achieved sufficient iodine reuptake 
to warrant treatment with 131I.  Interestingly, 5 of these patients were found to have NRAS 
mutations, one a BRAF mutation, one a RET/PTC rearrangement and one patient was wild-
type.  Further genotyping and cytogenetic analysis is ongoing to discover other potential 
oncogenic drivers that may have promoted susceptibility to this therapeutic strategy.  The 
increased iodine incorporation as quantified on the 124I scans translated to clinical efficacy 
with RAI therapy.  Reduction in tumour size by RECIST criteria was achieved in all RAI-
treated patients, with 5 confirmed partial responses and 3 patients with stable disease.  
Substantial decreases in serum thyroglobulin following RAI therapy were achieved in all 8 
RAI-treated patients.  The mean percent reduction in serum thyroglobulin achieved “post-
RAI” (2 months after RAI treatment) compared to “pre-RAI” (within 3 weeks before RAI 
treatment) was 89%.     


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Drug Substance Selumetinib (AZD6244)  
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Edition Number 4 
Date 01 July 2014 
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Data from the pilot study also suggests that pre-treatment with selumetinib selectively 
increased RAI uptake in tumoural lesions compared to non-thyroidal tissue (salivary gland). 
This pilot study demonstrates that MAPK pathway inhibition can modulate RAI uptake in the 
most difficult clinical scenario: patients with resistance to RAI therapy. Most patients in the 
pilot clinical study described above had many metastatic lesions, some of which were 
refractory to RAI at baseline, and some of which were partially RAI avid at baseline.  
Importantly, selumetinib not only restored RAI uptake in previously refractory lesions, but 
also increased RAI uptake in most partially-avid lesions (typically by more than 100% 
compared to the baseline value; 3 to 7 fold increases in maximum SUVs in such lesions were 
consistently observed). This provides a strong rationale to develop this strategy in the adjuvant 
setting for RAI naïve patients, with the goal of further enhancing what is more likely to be 
RAI-susceptible disease for patients at high risk of primary treatment failure.    
In addition to the pilot study described above, a phase II study of 100 mg bid selumetinib 
(previous mix-and-drink formulation) in 39 patients with RAI-refractory differentiated 
metastatic thyroid cancer has also been completed (Hayes et al 2012). This study involved 
continuous monotherapy dosing of selumetinib and no RAI treatment. The results 
demonstrated few clinical responses (one partial response in 32 evaluable patients), but 
demonstrated a 66% stable disease rate; median PFS in this poor-prognosis cohort was 
33 weeks in patients with mutations in BRAF V600E, and 32 weeks in all-comers. Although 
this study was conducted with the mix and drink formulation (from which selumetinib 
exposure may be lower), the efficacy of selumetinib as monotherapy in this population was 
disappointing. 
Taken together, these data suggest a strong rationale for investigating selumetinib with RAI in 
patients with DTC.  Given the known prevalence of MEK pathway activation in patients with 
DTC, and both the pre-clinical and clinical data seen when selumetinib is added to RAI, 
increasing iodine uptake, specifically with respect to selumetinib’s ability to upregulate NIS 
expression, adding selumetinib to standard of care RAI treatment has the potential to provide 
important clinical benefit.  This benefit may extend to all patients regardless of their genotype, 
or it may be greater in those patients with tumours driven by mutations in the MEK pathway. 
This study will allow these hypotheses to be tested. 
1.1.5.3 
Safety profile of selumetinib 
Array BioPharma was responsible for the first study of selumetinib into patients.  The 
remainder of the oncology clinical development programme is the responsibility of 
AstraZeneca.  Selumetinib is currently in phase II development, and has been used as both 
monotherapy and in combination with other anti-cancer agents, in a variety of adult solid 
tumour settings (eg, pancreatic cancer, colorectal cancer, melanoma and NSCLC), and 
paediatric cancer patients. 
The formulation taken into the phase I clinical programme by Array Biopharma was an 
extemporaneous preparation of an oral suspension of selumetinib as the free-base in an 
aqueous solution of sulphobutylether ȕ-cyclodextrin (SBE-CD, Captisol®), referred to as the 
free-base suspension formulation (mix and drink).  The AstraZeneca phase II monotherapy 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
27(120) 
clinical programme also utilised this formulation.  Subsequent formulation development 
resulted in a capsule formulation of selumetinib as the hydrogen sulphate salt (AZD6244 Hyd-
Sulfate), which will be used in this study. The maximum tolerated dose (MTD) for the 
suspension formulation was determined to be 100 mg twice daily, whereas for the capsule, the 
MTD was determined to be 75 mg twice daily. The emerging safety and tolerability profile of 
the capsule formulation is broadly consistent with that of the suspension formulation, although 
a higher frequency of fatigue and nausea has been reported with the capsule formulation 
compared to the suspension formulation in the phase II monotherapy studies. 
As of April 2012, over 1200 patients have received selumetinib as monotherapy or in 
combination with other anti-cancer agents in clinical studies (AstraZeneca and non 
AstraZeneca-sponsored studies, including investigator-sponsored studies). 
Two phase I studies (D1532C00005, D1532C00020) were performed with the Hyd-Sulfate 
formulation. Comparison of the frequencies from Study D1532C00005 and the AZ-sponsored 
phase II monotherapy studies described below, shows that there are higher percentages of 
patients reporting the most frequent AEs such as fatigue, dermatitis acneiform, diarrhoea, 
nausea and peripheral oedema with the Hyd-Sulfate formulation. This may be due to the 
higher plasma exposures achieved with the capsule formulation, but may also be in part as a 
consequence of the more heavily pre-treated patient population in study D1532C00005 having 
lower tolerances to developing toxicity. 
x
The frequencies of common AEs observed in Study D1532C00020 were generally 
more similar to that of Study D1532C00003 (free-base suspension formulation in a 
phase II population), which may mean that some of the differences in frequencies 
observed just reflect variations in the study population as the selumetinib safety 
profile is established. 
Two hundred and sixty nine (269) patients received selumetinib free base suspension 100 mg 
twice daily in 4 completed phase II monotherapy studies (D1532C00003, D1532C00008, 
D1532C00011, and D1532C00012). 
x
Rashes (including the preferred terms dermatitis acneiform, rash, rash 
maculopapular, rash macular, rash papular, acne, and folliculitis) were reported in 
approximately 70% of patients receiving treatment with selumetinib, and dermatitis 
acneiform was the most common AE term overall (54%).  Other commonly 
reported AEs were diarrhoea (49%), nausea (33%) and vomiting (24%).  Adverse 
events of peripheral oedema, periorbital oedema, and facial oedema were reported 
in 31%, 9%, and 4% of patients, respectively.  The AEs of fatigue or asthenia were 
reported in approximately 30% of patients in this phase II population.  Dyspnoea 
exertional or dyspnoea was reported in 13% of patients and, in individual studies, 
dyspnoea exertional was reported at a higher incidence in the selumetinib groups 
than in the comparator chemotherapy groups. 
x
Serious AEs were reported in 24% of patients receiving selumetinib monotherapy.  
The most frequently reported serious AEs were vomiting (1.5%), diarrhoea, 


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Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
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erysipelas, and pulmonary embolism (in 1.1% patients each).  Serious AEs of 
infections (bacterial sepsis, sepsis, infection, and bacterial arthritis) were reported in 
2.2% of patients. The most frequently related reported treatment-related SAE was 
vomiting (3 patients).  
x
In Study D1532C00003, small increases in blood pressure were observed after 1 
week on selumetinib, with mean increases of 7.4 mmHg (systolic, SBP) and 5.3 
mmHg (diastolic, DBP) at Week 8, compared with mean increases of 1.1 mmHg 
(SBP) and 0.5 mmHg (DBP) in the temozolomide comparator arm.  The AE of 
hypertension was reported in 18 patients (6.7%) receiving selumetinib in phase II 
monotherapy studies; 6 of these patients had hypertension at entry to the study, and 
a further 5 patients had documented risk factors for hypertension.  
x
Reversible asymptomatic reduction in left ventricular ejection fraction (LVEF) to 
below 55% has been reported in a small proportion of patients with advanced 
cancers in the monotherapy and randomised placebo controlled studies in 
combination with standard chemotherapies, with both formulations of selumetinib.  
In both placebo controlled studies no patient treated with selumetinib had severe 
LVEF impairment (< 35%) or symptomatic heart failure. Evidence of reversibility 
on continuing treatment with selumetinib has been demonstrated in some patients. 
LVEF scheduled assessments were only included in one phase II study 
(D1532C00003) and in the selumetinib group to evaluate a possible cardiac 
aetiology of the peripheral oedema reported in earlier studies. The median change in 
LVEF at Week 4 was 1.2 percentage points, and the individual change from 
baseline ranged from –20 to +19 percentage points. Adverse events of ejection 
fraction decreased, left ventricular dysfunction, or ventricular dysfunction were 
reported in a total of 5 patients (3.3%) receiving selumetinib (including 1 patient 
who had switched from temozolomide treatment after disease progression) versus 1 
patient (1%) in the comparator group.  
x
Review of clinical laboratory parameters in phase II monotherapy studies identified 
a trend toward increased alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) levels after starting treatment with selumetinib.  An 
increase in serum phosphate was observed in some patients after initiation of 
selumetinib, compared with patients randomised to comparator treatments.There 
was a trend toward a small mean decrease in albumin relative to the comparator.  
No other reports of selumetinib-related changes in laboratory parameters were 
considered to be of clinical relevance at this time.  There was no evidence of 
myelosuppression or renal impairment. 
x
Adverse events related to visual function have been reported across the programme 
with selumetinib.  Most often there were no specific clinical findings reported from 
patients that underwent ophthalmological evaluation after reporting the AE of visual 
disturbance.  AEs consistent with central serous retinopathy have been reported in a 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
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small number of patients receiving treatment with selumetinib, generally in 
combination with other anti-cancer agents.  
x
There have been reports of pneumonitis-type events in a small number of patients 
receiving treatment with selumetinib. An association with selumetinib has not been 
established. An algorithm for investigation of dyspneoa is provided in Appendix G: 
"Guidance for Management of Adverse Events in Studies of Selumetinib." 
x
Weakness of neck extensor muscles in conjunction with creatine phosphokinase 
(CPK) increases (reversible on treatment interruption) have been reported in 3 out 
of 54 patients with uveal melanoma receiving selumetinib 75 mg twice daily in one 
non-AstraZeneca sponsored study. Increases in CPK levels have been recorded in a 
small number of patients receiving treatment with selumetinib. CPK elevations are 
present in some patients with muscle symptoms, although asymptomatic elevations 
have also been reported. A relationship between selumetinib and elevated CPK 
levels or myopathy has not been established. 
In the DTC pilot study described in Section 1.1.5.2 (Ho et al 2012), where 20 metastatic 
thyroid cancer patients were treated with a 4 week course of selumetinib 75 mg twice daily, all 
events attributed to selumetinib were Grade 1 or 2, and included fatigue (80%), maculo-
papular rash (70%), acneiform rash (25%), elevation in AST (70%; all Grade 1), elevation in 
ALT (45%; all Grade 1), diarrhea (45%), nausea (40%), limb edema (30%), oral mucositis 
(35%), constipation (20%), hypoalbuminemia (15%), decreased white blood cell count (15%), 
face edema (10%), scalp pain (10%), decreased platelet count (1 patient; Grade 1), eye 
disorder (1 patient; Grade 1 consisting of visual halos and slight blurriness that resolved after 
therapy stopped), hypertension (1 patient; Grade 1), periorbital edema (1 patient; Grade 1), 
and vomiting (1 patient, Grade 1).  One patient who was treated with RAI was subsequently 
diagnosed with myelodysplastic syndrome 51 weeks after RAI administration which 
subsequently evolved into acute leukaemia (this was determined to be unrelated to selumetinib 
and likely related to cumulative RAI toxicity as well as previous external beam radiation 
therapy).  All adverse events were readily managed with supportive mediations and were 
reversible upon discontinuation of selumetinib.  None of the 20 patients required dose delays 
or reductions due to selumetinib toxicity.   
In the only other study to specifically investigate selumetinib in differentiated thyroid cancer 
patients (the phase II study of 100 mg bid selumetinib, previous mix-and-drink formulation) in 
39 patients with RAI-refractory differentiated metastatic thyroid cancer (Hayes et al 2012). In 
these patients with RAI-refractory disease, common drug-related AEs included rash (77%), 
fatigue (49%), diarrhea (49%), and peripheral oedema (36%).  Grade 3 and 4 AEs were 
consistent with those across the selumetinib program and also included rash (18%), fatigue 
(8%), diarrhea (5%) and peripheral oedema (5%).  Twelve patients required dose reductions 
for reported AEs across the length of the study (the duration of treatment was greater than 16 
weeks for 69% of patients).  Six patients (15%) discontinued treatment due to adverse events. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
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A study of selumetinib in combination with radiation in patients with non-small cell lung 
cancer has recently been opened but no safety or efficacy results are yet available from this 
study.  
Selumetinib is not mutagenic or clastogenic in vitro but produced increases in micronucleated 
immature erythrocytes in mouse bone marrow micronucleus studies.  Investigatory studies 
show that this is predominantly via an aneugenic mechanism which is consistent with 
disruption of normal spindle function as a consequence of the known pharmacological action 
of a MEK inhibitor.  With selumetinib Hyd-Sulfate, a NOEL of 24 mg/kg/day (for 2 days) 
was established for induction of micronuclei, with plasma exposures significantly above those 
observed in cancer patients at the maximum tolerated dose of 75 mg twice daily.  This 
suggests that selumetinib will have little potential to cause aneugenicity in dividing cell 
populations in patients at the proposed clinical dose.  Thus, any additional aueugenic risk from 
a 5 week course (maximum 43 days) of twice daily 75 mg selumetinib dosing in this 
potentially curative patient setting, is considered to be negligible in comparison with the 
known and more substantial risk from radiation exposure following a therapeutic dose of 131I 
(100 mCi) that patients will receive as part of standard of care.    
In summary, selumetinib has been shown to have an acceptable profile of side effects, in an 
extensive safety database for a compound at this stage of development.   
Further details regarding the safety profile of selumetinib can be found in the Investigator 
Brochure.   
1.1.5.4      The pharmacokinetics of Selumetinib in subjects of Asian ethnicity 
Plasma exposure of Selumetinib (Cmax and AUC) is higher, at a population level, in subjects 
of Asian ethnicity by approximately 1.5- to 2-fold in non-Japanese Asians and Japanese 
subjects, compared with Western subjects.  However, the pharmacokinetics of Selumetinib 
show considerable variation and there is overlap in the range of exposure experienced by 
Asian and Western subjects (some individual Asian subjects have similar plasma levels to 
those in Western subjects).  The higher average plasma exposure was not associated with a 
change in the tolerability profile of single dose Selumetinib.   
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 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
31(120) 
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 
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. 
 
1.2 
Research hypothesis 
Pre-treatment with selumetinib enhances the uptake of radioactive iodine in differentiated 
thyroid cancer, resulting in a greater incidence of complete remission after adjuvant RAI 
therapy in patients at high risk of primary treatment failure. 
1.3 
Rationale for conducting this study 
Unfortunately a significant proportion of thyroid cancer patients are not cured by their initial 
surgery and RAI therapy. This is often due to the inability of their cancer cells to adequately 
incorporate RAI (due to reduced expression of NIS). In such cases, repeated administration of 
RAI may be given (for RAI avid disease) with the aim of inducing remission and curing their 
disease. This outcome however is not guaranteed, and patients who subsequently develop 
refractory metastatic disease have a much poorer prognosis and may eventually succumb to 
their disease; at least one third of patients who develop metastatic disease have no or very low 
uptake and are thus not amenable to further RAI treatment.  There is thus an urgent need for a 
medicine that can enhance the effectiveness of initial RAI treatment and increase the 
probability of achieving remission, thereby preventing more patients from developing distant 
metastatic disease.  
1.4 
Benefit/risk and ethical assessment 
It is clear from the Investigator-sponsored study (Ho et al 2012), that a short course of 
selumetinib prior to RAI therapy, is effective in enhancing RAI uptake, reducing tumour 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
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marker (Tg) levels, and reducing tumour size in heavily pre-treated patients with documented 
RAI-refractory disease. Most patients in the pilot clinical study had numerous metastatic 
lesions, some of which were refractory to RAI at baseline and some of which were partially 
RAI avid at baseline.  Importantly, selumetinib pre-treatment not only restored RAI uptake in 
previously refractory lesions, but also increased RAI uptake in the majority of partially avid 
lesions (typically by more than 100% compared to the baseline value; 3- to 7-fold increases in 
maximum SUVs in such lesions were consistently observed). This pilot data not only supports 
the preclinical hypothesis that inhibiting the MAPK pathway can convert non-RAI avid 
lesions to RAI avid tumours, but also demonstrates that iodine uptake in previously iodine 
sensitive lesions can be significantly increased with selumetinib.  This observation broadens 
the potential clinical applicability of this approach beyond just RAI-refractory thyroid cancer, 
to the use of selumetinib and RAI as part of upfront adjuvant treatment of RAI-naïve and 
susceptible DTC.  
The potential benefit to patients in this study is therefore high, with an increased chance of 
complete remission. The toxicity risk from a short course (approximately 5 weeks) of 
selumetinib treatment has been carefully considered for this potentially curative population; 
the side effect profile of selumetinib in the short timeframe (maximum 6 weeks of exposure) 
is considered to be predictable, manageable and reversible (mainly rash and fatigue). The long 
term risk of secondary malignancies associated with RAI is considered low from a single 
100 mCi dose, as these are rare and more typically develop following cumulative RAI 
treatments and exposure. Patients under the age of 18 years will be excluded to minimise any 
risk of increased radioactivity exposure in a younger population. The side effect profile of 
both selumetinib and RAI will be monitored over the entire 3 year study duration for each 
patient. 
2. 
STUDY OBJECTIVES 
2.1 
Primary objective 
To compare the efficacy of selumetinib with radioactive iodine therapy (RAI), versus placebo 
with RAI, by assessment of complete remission rate at 18 months post RAI treatment in the 
intention to treat (ITT) study population. Complete remission is defined in Section 6.4.1. 
2.2 
Secondary objectives 
1. 
To compare the efficacy of selumetinib with RAI, versus placebo with RAI, by 
assessment of complete remission rate at 18 months post RAI treatment in a sub-group 
of patients with tumours known to be mutation positive for BRAF or NRAS (defined in 
Section 6.10.1). Complete remission is defined in Section 6.4.1. 
2. 
To compare the efficacy of selumetinib with RAI, versus placebo with RAI by 
assessment of clinical remission rate at 18 months post RAI treatment in the ITT study 
population. Clinical remission is defined in Section 6.4.6. 


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Edition Number 4 
Date 01 July 2014 
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3. 
To compare the efficacy of selumetinib with RAI, versus placebo with RAI by 
assessment of clinical remission rate at 18 months post RAI treatment in a sub-group 
of patients with tumours known to be mutation positive for BRAF or NRAS (defined in 
Section 6.10.1). Clinical remission is defined in Section 6.4.6. 
4. 
To assess the safety and tolerability of selumetinib with RAI compared to placebo with 
RAI. 
5. 
To investigate the pharmacokinetics (PK) of selumetinib and N-desmethyl selumetinib 
when administered to patients with differentiated thyroid cancer. 
2.3 
Exploratory objectives 
1. 
To explore subsequent thyroid cancer therapy given to patients who receive  
selumetinib with RAI, or placebo with RAI. 
2. 
To investigate the relationship between selumetinib and/or N-desmethyl selumetinib 
plasma concentrations/exposure and clinical outcomes, efficacy, AEs and/or safety 
parameters. 
3. 
To collect tumour, plasma and serum samples for potential future research on 
biomarkers relevant to DTC and response and resistance to study treatments.  
4. 
To collect and store DNA for future exploratory research into genes/genetic variation 
that may influence response (ie, distribution, safety, tolerability and efficacy) to 
selumetinib or RAI and/or susceptibility to cancer. 
The exploratory analysis will be reported separately from the CSR. 
3. 
STUDY PLAN AND PROCEDURES 
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
standard procedures. 
3.1 
Overall study design and flow chart 
This is a double-blind, randomised, placebo-controlled study to assess the efficacy and safety 
of a short course (approximately 5 weeks) of selumetinib (75 mg, orally twice daily) in 
combination with adjuvant RAI therapy compared to placebo and adjuvant RAI therapy, in 
patients with differentiated thyroid cancer at high risk of primary treatment failure. 
Approximately 228 patients will be randomised 2:1 selumetinib to placebo. 
This will be a multi-centre, international study; it is anticipated that approximately 50 centres 
will recruit patients in South and/or North America and Europe.  


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Edition Number 4 
Date 01 July 2014 
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3.1.1 
Treatment Plan 
Following randomisation, patients will take their assigned study treatment (selumetinib or 
placebo) for a period of approximately 5 weeks, twice daily.  Study treatment will begin 
approximately 4 weeks prior to the planned day of RAI therapy. Refer to Table 2 for an 
example study treatment plan. The following treatment criteria must be adhered to: 
1. 
Day 1 of study treatment must occur: 

no earlier than 6 weeks after the patient’s thyroid cancer surgery (their 
last surgery if it was a 2-stage thyroidectomy), and   

no later than 16 weeks after the patient’s thyroid cancer surgery (their last 
surgery if it was a 2-stage thyroidectomy).   
2. 
Patients should remain on study treatment continuously for a minimum of 7 
consecutive days prior to their planned RAI therapy, on the day of RAI therapy, and 
for 5 consecutive days afterwards.  If necessary, RAI therapy may be rescheduled at 
the discretion of the Investigator to allow the patient to receive study treatment for a 
minimum of 7 consecutive days beforehand. 
3. 
Study treatment with selumetinib or placebo will typically last for 36 days, but must 
be for no longer than 43 days. The planned RAI can be postponed by up to 1 week 
if absolutely necessary. 
4. 
Patients will be required to adhere to a low iodine diet for a period of 1 week before 
their planned RAI adjuvant treatment, until the day after their RAI treatment. Refer 
to Section 5.1.1 and the example diet in Appendix F for further details. 
5. 
For each of the 2 days immediately prior to their planned RAI therapy, patients will 
receive a recombinant human TSH injection (rhTSH, Thyrogen), in order to 
stimulate iodine uptake (refer to Section 5.5.4 for details). 
6. 
Following the 2 days of rhTSH injections, patients will receive their planned RAI 
therapy the immediate next day (refer to Section 5.5.4 for further RAI dosing 
information).   
7. 
Twice daily dosing of selumetinib/placebo should continue for 5 days following 
RAI therapy. 
8. 
If a patient suspends study drug (selumetinib or placebo) treatment for more than 14 
days they are no longer eligible to re-start the treatment but will be followed 
according to the study plan.


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
35(120) 
Table 2 
Example study treatment plan  
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Sunday 
Day 1 
X 
Day 2 
X 
Day3 
X 
Day 4 
X 
Day 5 
X 
Day 6 
X 
Day 7 
X 
Day 8 
X 
Day 9 
X 
Day 10 
X 
Day 11 
X 
Day 12 
X 
Day 13 
X 
Day 14 
X 
Day 15 
X 
Day 16 
X 
Day 17 
X 
Day 18 
X 
Day 19 
X 
Day 20 
X 
Day 21 
X 
Day 22 
X 
Day 23 
X 
Day 24 
X 
Low I diet 
Day 25 
X 
Low I diet 
Day 26 
X 
Low I diet 
Day 27 
X 
Low I diet 
Day 28 
X 
Low I diet 
Day 29 
X 
Low I diet 
Thyrogen 
Day 30 
X 
Low I diet 
Thyrogen 
Day 31 
X 
Low I diet 
RAI 
Day 32 
X 
Low I diet 
Day 33 
X 
Day 34 
X 
Day 35 
X 
Day 36 
X  
last day of 
study 
treatment 
 
Day 38  
(Day 36-41) 
WBS scan 
 (3-10 days 
after RAI 
dose) 
 
 
 
 
 X: Study treatment administration (selumetinib or placebo, twice daily) 
RAI: radioactive iodine therapy (131I) refer to Section 5.5.4.2 for details 
This suggested treatment plan is an example only. The treatments may be planned for different days as long as all 
criteria in Section 3.1.1 are met. 
 
3.1.2 
Follow-up plan 
Following completion of RAI therapy and planned discontinuation of study treatment 
(randomised selumetinib or placebo); patients will be followed up as follows: 
1. 
3-10 days after RAI therapy, patients will undergo a post-therapy whole body RAI 
(131I) nuclear medicine scan to determine where the RAI has localized in the body 
(refer to Section 6.4.4.2 for further detail). 
2. 
Patients will be monitored for TSH and thyroxine (T4) levels as per local standard 
of care (refer to Section 6.4.3.3 for further detail). Note that T4 levels will not be 
collected in the study database. 
3. 
At 9 months (±3 months) following RAI treatment, patients will be assessed for: 
(a) 
TSH-suppressed Tg and Tg antibody levels (TgAb).  Refer to Section 5.9.1.1 
for further details. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
36(120) 
(b) 
Neck ultrasound (US). Refer to Section 5.9.1.2 for further details. 
It is important that these assessments are not performed earlier than 6 months after 
RAI treatment.  
4. 
Patients will be assessed for their complete remission status at the primary endpoint 
18 months following their RAI treatment.  A staged approach to the primary 
endpoint assessments will be used in this study in order to determine remission 
status (presence or absence of thyroid cancer), such that each patient may not 
require all assessments. Refer to Section 6.4, Table 4 and Figure 3 for further 
details. The primary endpoint assessments must be started 18 months ± 2 weeks 
following the patient’s RAI dose, and all necessary primary endpoint assessments 
must be completed within an 8 week period. 
Further thyroid cancer therapy (eg, additional surgery, RAI re-treatment, external 
beam radiotherapy or systemic therapy) should only be given during the initial 
18 month follow-up period according to the re-treatment criteria in Section 5.9. Any 
patient that is re-treated in the 18 month period following their RAI therapy will not 
require any primary endpoint assessments performing (they will be determined not 
to be in complete remission for the purpose of the study and will enter standard of 
care follow up, remaining in the study until the 3 year follow up). 
5. 
Following the primary endpoint assessments (or re-treatment), all randomised 
patients will be further followed-up at 3 years following their RAI treatment.  It is 
the responsibility of the study investigator to ensure they conduct follow-up as 
described in this protocol if patients transfer to non-study hospitals, or if patients are 
discharged for routine follow up at other institutions (eg, family doctor or local non-
specialist hospital). 
Assessments planned at each visit are detailed in Table 3, Table 4 and Section 6. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
37(120) 
Figure 1 
Study flow chart  
 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
38(120) 
Table 3 
Study Plan 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Visit Description 
Screening 
Randomi
sation 
On -
treatment 
safety 
visit 
Thyrogen 
RAI 
therapy 
Last day 
of 
treatment 
30 days 
post 
treatment 
4 Month 
safety 
follow up 
9 
Month 
FU 
Primary 
endpoint 
assessmentsa 
27 
Month 
safety 
follow up 
3 Year 
FU 
Protocol 
Section 
Timing 
Day  
-28 to –1 
Day 1 
Day 14 
Days  
29 & 30 
Day 31 
 Day 36 
Week 10 
4 months 
post RAI 
(visit 5) 
9 
months 
post 
RAI 
(visit 5) 
18 months 
post RAI 
(visit 5) 
27 
months 
post RAI 
(visit 5) 
3 years 
post 
RAI 
(visit 5) 
 
Visit Window 
N/A 
N/A 
±1wk 
+1wk 
+1wk 
+1wk 
± 2 days 
± 2 
weeks 
± 3 
months 
Refer to 
Table 4 
± 2 
months 
± 1 
month 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
X 
X 
(Day 29 
or 30) 
 
 
X 
 
 
 
 
 
6.5.6 
Additional screening 
procedures  
X 
 
 
 
 
 
 
 
 
 
 
 
6.2 
Provision of archival 
tumourb 
 
X 
 
 
 
 
 
 
 
 
 
 
6.10.1.
1 
Plasma/serum sample for 
exploratory analysisb 
 
X (pre-
dose) 
 
 
 
 
 
 
 
 
 
 
6.10.2 
Pregnancy test 
X 
 
 
 
X 
 
 
 
 
Xa 
 
 
6.5.9.1 
Optional genetic consent & 
sample (whole blood)  
 
X (pre-
dose) 
 
 
 
 
 
 
 
 
 
 
6.9 
Adverse eventsc 
X 
 
 
 
 
 
 
 
 
 
 
 
6.5.3 
Concomitant medications 
X 
 
 
 
 
 
 
 
 
 
 
 
5.6 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
39(120) 
Table 3 
Study Plan 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Visit Description 
Screening 
Randomi
sation 
On -
treatment 
safety 
visit 
Thyrogen 
RAI 
therapy 
Last day 
of 
treatment 
30 days 
post 
treatment 
4 Month 
safety 
follow up 
9 
Month 
FU 
Primary 
endpoint 
assessmentsa 
27 
Month 
safety 
follow up 
3 Year 
FU 
Protocol 
Section 
Timing 
Day  
-28 to –1 
Day 1 
Day 14 
Days  
29 & 30 
Day 31 
 Day 36 
Week 10 
4 months 
post RAI 
(visit 5) 
9 
months 
post 
RAI 
(visit 5) 
18 months 
post RAI 
(visit 5) 
27 
months 
post RAI 
(visit 5) 
3 years 
post 
RAI 
(visit 5) 
 
Visit Window 
N/A 
N/A 
±1wk 
+1wk 
+1wk 
+1wk 
± 2 days 
± 2 
weeks 
± 3 
months 
Refer to 
Table 4 
± 2 
months 
± 1 
month 
 
Telephone follow up for 
safetyd 
 
 
 
 
 
 
 
X 
 
 
X 
 
6.5.3 
Vital signs (including height 
at screening), weight 
X 
X (pre-
dose) 
X 
X 
(Day 29 
or 30) 
 
 
X 
 
 
 
 
 
6.5.8 
Clinical chemistry 
X 
X (pre-
dose) 
X 
X 
(Day 29 
or 30) 
 
 
X 
 
 
 
 
 
6.5.5 
Haematology 
X 
X (pre-
dose) 
X 
X 
(Day 29 
or 30) 
 
 
X 
 
 
X 
 
X 
6.5.5 
Urinalysis  
X 
 
X 
 
 
 
X 
 
 
 
 
 
6.5.5 
ECGe 
X 
X 
 
Xe (Day 
29 or 30) 
 
 
X 
 
 
 
 
 
6.5.7.2 
ECHO/MUGAf 
X 
 
 
 
 
 
X 
 
 
 
 
 
6.5.7.1 
Ophthalmologic 
examinationf 
X 
 
 
 
 
 
X 
 
 
 
 
 
6.5.9.2 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
40(120) 
Table 3 
Study Plan 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Visit Description 
Screening 
Randomi
sation 
On -
treatment 
safety 
visit 
Thyrogen 
RAI 
therapy 
Last day 
of 
treatment 
30 days 
post 
treatment 
4 Month 
safety 
follow up 
9 
Month 
FU 
Primary 
endpoint 
assessmentsa 
27 
Month 
safety 
follow up 
3 Year 
FU 
Protocol 
Section 
Timing 
Day  
-28 to –1 
Day 1 
Day 14 
Days  
29 & 30 
Day 31 
 Day 36 
Week 10 
4 months 
post RAI 
(visit 5) 
9 
months 
post 
RAI 
(visit 5) 
18 months 
post RAI 
(visit 5) 
27 
months 
post RAI 
(visit 5) 
3 years 
post 
RAI 
(visit 5) 
 
Visit Window 
N/A 
N/A 
±1wk 
+1wk 
+1wk 
+1wk 
± 2 days 
± 2 
weeks 
± 3 
months 
Refer to 
Table 4 
± 2 
months 
± 1 
month 
 
Selumetinib/placebo dosingg 
 twice daily 
 
 
 
 
 
 
 
 
 
 
 
 
5.5.2 
PK blood samplesh 
 
X 
 
Xh (Day 
29 or 30) 
 
 
 
 
 
 
 
 
6.7 
Low iodine dieti 
 
 
 
X 
X 
 
 
 
 
Xa 
 
 
5.1.1 
Thyrogen injection 
 
 
 
Xx2 
(Day 29 
and 30) 
 
 
 
 
 
Xx2a 
 
 
5.5.4.1 
131I (RAI) treatment  
single 100 mCi dose 
 
 
 
 
X 
 
 
 
 
 
 
 
5.5.4.2 
131I 5 diagnostic dose for 
WBS 
single 5 mCi dose 
 
 
 
 
 
 
 
 
 
Xa 
 
 
5.5.4.2 
131I nuclear medicine WBS 
scan 
 
 
 
 
 
Xj 
 
 
 
Xa 
 
 
6.4.4.2 
Re-treatment assessmentk 
 
 
 
 
 
 
 
 
X 
X 
 
X 
5.9 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
41(120) 
Table 3 
Study Plan 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
Visit Description 
Screening 
Randomi
sation 
On -
treatment 
safety 
visit 
Thyrogen 
RAI 
therapy 
Last day 
of 
treatment 
30 days 
post 
treatment 
4 Month 
safety 
follow up 
9 
Month 
FU 
Primary 
endpoint 
assessmentsa 
27 
Month 
safety 
follow up 
3 Year 
FU 
Protocol 
Section 
Timing 
Day  
-28 to –1 
Day 1 
Day 14 
Days  
29 & 30 
Day 31 
 Day 36 
Week 10 
4 months 
post RAI 
(visit 5) 
9 
months 
post 
RAI 
(visit 5) 
18 months 
post RAI 
(visit 5) 
27 
months 
post RAI 
(visit 5) 
3 years 
post 
RAI 
(visit 5) 
 
Visit Window 
N/A 
N/A 
±1wk 
+1wk 
+1wk 
+1wk 
± 2 days 
± 2 
weeks 
± 3 
months 
Refer to 
Table 4 
± 2 
months 
± 1 
month 
 
Blood sample for TSH  
 
 
 
 
 
 
 
 
X 
X  
 
 
6.4.3.3 
Blood sample for 
suppressed Tg 
 
 
 
 
 
 
 
 
Xn 
X 
 
 
6.4.3.1 
Blood sample for TgAb 
X 
 
 
 
 
 
 
 
X 
X 
 
 
6.4.3.4 
Blood sample for rhTSH-
stimulated Tg 
 
 
 
 
 
 
 
 
 
Xa 
 
 
6.4.3.2 
Neck ultrasound 
Xl 
 
 
 
 
 
 
 
X 
X 
 
 
6.4.4.1 
Neck MRI 
Xl 
 
 
 
 
 
 
 
 
Xa 
 
 
6.4.4.3 
Chest CT without contrast  
Xl 
 
 
 
 
 
 
 
 
Xa 
 
 
6.4.4.4 
Final follow-up assessment 
of clinical status 
 
 
 
 
 
 
 
 
 
 
 
X 
6.4.8 
Biopsy/FNA for disease 
confirmation 
 
 
 
 
 
 
 
 
Xm 
Xm 
 
 
6.4.4.5 
Tumour biopsy on 
progression (optional) 
Optional sample on disease progression (for example, if the patient is re-treated for persistent or recurrent thyroid cancer, or has further surgery). 
Note that both a plasma and serum sample for exploratory analysis should also be taken on disease progression. 
6.10.3 
6.10.2 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
42(120) 
Study Plan Table 3 Footnotes 
a Refer to Table 4 and Section 6.4.2. 
b  Provision of these samples is mandatory in this study. Samples should also be obtained on progression (refer to Section 6.10.2). 
c All AEs/SAEs should be collected from the day of consent until 30 days following the last dose of study treatment. From then on, all SAEs (regardless of 
causality), and all AEs related to either RAI, or the combination of RAI and study treatment, should be collected until the last study visit 3 years 
following the patient’s RAI dose. The same AE collection scheme applies for any re-treated patient.  
d The Investigator (or delegate) is required to contact the patient by telephone to follow up for any safety information (according to the collection scheme 
detailed in Section 6.5). For re-treated patients, safety follow-up should continue according to the protocol-scheduled visits, but may be collected by 
telephone if necessary at each visit (refer to Section 5.9). 
e Single ECG assessments 1-2 hours following the first dose on Day 1 and Day 29 or Day 30 of study treatment. A single ECG assessment is also required 
whenever an ECHO/MUGA is performed, on any cardiorespiratory AE, and for premature discontinuation. 
f These assessments must also be performed on symptomatology according to the relevant protocol section. 
g Study treatment must be initiated no earlier than 6 weeks after the patient’s thyroid cancer surgery, and no later than 16 weeks after the patient’s thyroid 
cancer surgery (their last surgery if it was a 2-stage thyroidectomy). 
h Each patient will be asked to contribute 8 PK blood samples, one from each of the four pre defined time windows on both Day 1 and Day 29 or Day 30.  The 
Day 29 or Day 30 PK blood samples may be taken earlier, from Day 22 onwards of study treatment if preferred, but it is essential that all PK blood 
samples are collected before the RAI dose is administered. (a) Pre-dose (within 15 minutes of dosing), (b) between 15 minutes and 1 hour post-dose, (c) 
between 1.5 and 2.5 hours post-dose, and (d) between 3 and 8 hours post-dose. 
i  All patients must adhere to a low iodine diet (an example diet is provided in Appendix F). 
j The post-RAI WBS may be performed any time from 3-10 days following the patient’s RAI dose (thus it does not have to be on the same day as the last dose 
of study treatment). 
k The re-treatment assessment will establish whether the patient has received any further treatment for thyroid cancer. Refer to Section 5.9 for the study 
criteria for re-treatment in the initial 18 months following the patient’s RAI dose. 
l The post-operative imaging assessments must be performed no sooner than 4 weeks post-surgery, and after all other screening assessments have been 
performed (ie, they should not be performed for any patient that is otherwise ineligible).  
m Only if required (refer to Section 6.4.4.5) 
n A repeat sample for suppressed Tg may be required 2-4 weeks later, refer to Section 5.9.1.1. 
For imaging data that is required to be sent to the central imaging CRO at any point in the study refer to Section 6.4.4.5. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
43(120) 
Table 4 
Study Plan for the 18 month Primary Endpoint Assessments 
A staged approach to the primary endpoint assessments will be used in this study in order to determine remission status (absence of 
thyroid cancer), such that each patient may not require all assessments. Full details are outlined in Section 6.4.2. 
 
Stage 1 
Stage 2 
Stage 3 
Protocol Section 
Time window 
Stage 1 assessments must be started 18 months ± 2 weeks following the patient’s RAI 
dose, and all necessary primary endpoint assessments must be completed within an 8 
week period. 
6.4.2 
Thyroid cancer re-treatment assessmenta 
Xa 
 
 
5.9 
Suppressed Tg  
X 
 
 
6.4.3.1 
TSH 
X 
 
 
6.4.3.3 
TgAbb 
Xb 
Xb 
 
6.4.3.4 
Neck USf 
X 
 
 
6.4.4.1 
Biopsy or FNAd 
Xd 
 
 
6.4.4.5 
Haematology 
X 
 
 
6.5.5 
Low iodine diete 
 
Xe 
 
5.1.1 
Thyrogen injectionc 
 
X x 2c 
 
5.5.4.1 
Stimulated Tgc 
 
Xc 
 
6.4.3.2 
Pregnancy test 
 
X 
 
6.5.9.1 
Diagnostic 5mCi 131I dosec 
 
Xc 
 
5.5.4.2 
WBS (nuclear medicine scan)c, f 
 
Xc 
 
6.4.4.2 
Neck MRI with contrastf 
 
 
X 
6.4.4.3 
Chest CT without contrastf 
 
 
X 
6.4.4.4 
Selumetinib/RAI-related AE/SAEs  
 
 
 
6.5.3 
 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
44(120) 
Footnotes for Table 4: Study Plan for the 18 month Primary Endpoint Assessments 
a Patients that have been re-treated for thyroid cancer between their initial RAI dose and the primary endpoint assessments 18 months later (refer to Section 
5.9 for re-treatment criteria), will not have any primary endpoint assessments performed, they will remain in the study and enter standard of care follow 
up according to local practice. They should still be followed up for safety information at 18 m, 27 m and 3 years following their initial RAI dose. 
b For decision making purposes at any time in the study, standardised central analysis results must be used. If the stage 1 blood sample is positive for TgAb, 
but the stage 2 blood sample is negative for TgAb, then a third blood sample 10 days later (± 3 days) is required to confirm absence of TgAb.  
c Patients will receive 2 Thyrogen injections on consecutive days (day 1 and 2), followed by a diagnostic dose (5mCi) of 131I on either day 2 or day 3, and a 
blood draw for stimulated Tg central assessment and WBS both on day 5.  
d Only if required to prove absence of disease for suspicious lesions (refer to Section 6.4.4.5). 
e Patients will be required to adhere to a low iodine diet for a period of 1 week before their planned RAI adjuvant treatment, until the day after their RAI 
treatment. Refer to Section 5.1.1 and the example diet in Appendix F for further details. 
f For imaging data that is required to be sent to the central imaging CRO refer to Section 6.4.4.5.


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
45(120) 
3.2 
Rationale for study design, doses and control group 
This study is designed to determine the efficacy of a 5-week course of selumetinib or placebo, 
and adjuvant RAI therapy, by assessing the rate of complete remission at 18 months post-RAI 
therapy.  
The dose and duration of selumetinib treatment in this study (75 mg twice daily for 5 weeks) 
is selected to be consistent with the pilot study, which has previously demonstrated enhanced 
RAI uptake following selumetinib treatment, reduction in Tg levels, and reduced tumour size 
following RAI therapy, in patients with RAI-refractory metastatic thyroid cancer (Ho et al 
2012).  In addition to the effects of selumetinib on the sodium iodine transporter (refer to 
Section 1.1.5.1), selumetinib may also increase levels of thyroid peroxidase and thyroglobulin 
in any remaining thyroid cells. These proteins are required to organify and retain iodide in 
thyroid cells, thus facilitating greater retention of 131I, and a higher dose of radiation to cancer 
cells. For this reason, patients will remain on selumetinib treatment for 5 days after receiving 
the therapeutic dose of RAI. 
Since RAI is the standard of care for this patient population, the selumetinib/RAI treatment 
group will be compared to a placebo/RAI control group for all study endpoints. 
The population who will participate in this study will be patients with differentiated thyroid 
cancer at high risk of primary treatment failure that would routinely require RAI adjuvant 
therapy as standard of care. This risk-stratified population has been selected because it is 
known that they are at an increased risk of failing to achieve remission following standard 
initial therapy, and therefore require more effective treatment strategies (refer to Section 
1.1.3). This study is intended to be an adjuvant therapy trial for patients without known 
structural persistent disease; patients with known distant metastases at screening will be 
excluded in order to minimise heterogeneity of the efficacy recorded.  
A secondary efficacy endpoint will be assessed in patients with tumours carrying BRAF or 
NRAS mutations, as these are known to constitutively activate the MEK signalling pathway. 
Treatment with a MEK inhibitor may thus be hypothesised to deliver a greater treatment effect 
in these patients. However, the pathway can be activated in many ways such that these 
patients are not likely to be the only population to benefit. Incorporation of a genetically 
predefined study population enables this hypothesis to be examined (mutation analysis of 
samples to identify the genetically predefined study population will be performed post-
randomisation, and prior to data base lock for the primary endpoint data analysis). 
Enhancing RAI uptake into thyroid cancer cells has the potential to increase the incidence of 
complete remission following RAI treatment. It has been shown that the incidence of 
complete remission following initial RAI treatment correlates with long-term outcome, and if 
complete remission has not been achieved, further treatment is frequently administered 
(Castagna et al 2011, Tuttle et al 2010).    
A study has retrospectively evaluated the time to nadir Tg in 299 patients who did not receive 
additional therapy after total thyroidectomy and RAI (Padovani et al 2012).  This patient 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
46(120) 
population includes both patients with no evidence of disease (remission) and patients with 
low level disease who are being observed (median follow up time is 7 years).  Figure 2 
illustrates that 94% of the 223 patients with no evidence of disease achieved a suppressed Tg 
level of < 1 ng/mL (the biochemical component of remission) by 18 months after initial RAI 
therapy. Therefore, it is expected that most patients who are likely to achieve remission in 
both arms will have done so by this time (for the purpose of this study both biochemical and 
structural absence of disease will be assessed).  Longer follow-up would not be expected to 
change the conclusions regarding an efficacy difference between the two study arms. In 
patients with similar characteristics to those planned in this study, a similar pattern and extent 
of Tg decline is also seen (Tuttle RM, unpublished sub-analysis of data from Padovani et al 
2012).  Previous studies have used time-points ranging from 8 to 24 months to assess 
remission rates after primary treatment of surgery and RAI (Castagna et al 2011, Tuttle et al 
2010, Vaisman et al 2012).   
Taking all the data into consideration, the incidence of complete remission at 18 months 
following initial RAI therapy has been selected as the primary endpoint for the proposed 
study.  Each randomised patient will be followed beyond their 18 month primary endpoint 
assessment, until 3 years after their RAI treatment, in order to further assess both the clinical 
status of patients, and the safety profile of selumetinib and RAI beyond the primary analysis 
(refer to Section 6.4.8).   
Figure 2 
Time course to achieving a suppressed Tg<1 ng/mL in patients 
receiving total thyroidectomy and RAI therapy 
 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
47(120) 
4. 
PATIENT SELECTION CRITERIA 
Investigator(s) should keep a record, (eg, patient screening log), of patients who entered pre-
study screening.  
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule. 
4.1 
Inclusion criteria 
For inclusion in the study patients should fulfil the following criteria: 
1. 
Provision of informed consent prior to any study specific procedures. The main 
study consent will include mandatory consent to provide a sample of archival 
tumour material.  
2. 
Males and females aged 18 years or above. 
3. 
Patients with histologically or cytologically confirmed follicular cell derived 
differentiated thyroid cancer including papillary thyroid cancer and all variants, 
follicular thyroid cancer and all variants, and poorly differentiated thyroid cancer.  
4. 
Note: Patients with a diagnosis of Hürthle cell carcinoma should be excluded. These 
are defined as having an invasive tumour composed of >75% of oncocytic (Hürthle) 
cells lacking the nuclear features of papillary carcinoma, tumor necrosis and marked 
mitotic activity. Patients with oncocytic (Hürthle cell variants) of papillary thyroid 
carcinoma defined as a tumour composed of a majority of oncocytic (Hürthle) cells 
having the nuclear features of papillary carcinoma are eligible to participate. 
5. 
Patients presenting with any one of the following staging categories post-surgery: 
(a) 
Primary tumour greater than 4 cm  
(b) 
Primary tumour of any size with gross extrathyroidal extension outside the 
thyroid gland (T4 disease) 
(c) 
N1a or N1b disease with at least 1 lymph node  1 cm 
(d) 
N1a or N1b disease involving 5 or more lymph nodes (of any size) 
Note: Patients with known metastatic disease at screening will be ineligible for this 
study as per the exclusion criteria. 
6. 
Patients must have had a one or two-stage total thyroidectomy with therapeutic neck 
dissection of any clinically apparent metastatic lymph nodes (levels I to VII of the 
lateral and central neck). All known tumour must have been resected.  


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
48(120) 
Note, the optimal surgical procedure is based on the findings from preoperative 
ultrasound, to identify the extent of lymph node metastases and thereby facilitate 
compartment-oriented neck dissection for complete surgical removal of all gross 
disease. Prophylactic neck dissection is not required or encouraged, but may be 
performed at the discretion of the treating surgeon. As the surgical procedure(s) will 
have been performed before study consent, any patient for whom a total 
thyroidectomy cannot be verified must be excluded from the study (note that 
patients having undergone a robotic or endoscopic thyroidectomy, or any other 
novel or remote access surgical technique must also be excluded). For patients who 
have had a two-stage thyroidectomy, the second surgical procedure must have taken 
place no later than 12 weeks after the first procedure, otherwise the patient is not 
eligible. 
7. 
Patients must have all of the following post-operative assessments performed no 
sooner than 4 weeks post-surgery (post their last surgery if it was a 2-stage 
thyroidectomy) and the results from each must verify the absence of macroscopic 
disease: 
(a) 
Neck US exam  
(b) 
Neck MRI with contrast 
(c) 
Chest CT without contrast 
Refer to Section 6.3 for further details. These assessments must be performed within 
the 28 day screening period (but ideally after all other screening assessments have 
been performed, ie, they should not be performed for any patient that is otherwise 
ineligible). 
8. 
Patients must be suitable for radioactive iodine therapy. 
9. 
Patients must be suitable for TSH suppression with a goal of 0.5 mIU/L TSH for 
the duration of the study (this may exclude some patients with cardiac conditions or 
osteoporosis). 
10. 
Patients must be willing and able to start study treatment within 16 weeks of their 
thyroid cancer surgery (their last surgery if it was a 2-stage thyroidectomy). Note 
that study treatment must not be initiated within 6 weeks of the patient’s last 
surgery. 
11. 
WHO or ECOG Performance Status 0 or 1. 
12. 
Females must: 
(a) 
be using adequate contraceptive measures (refer to Section 5.1.2),   


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(b) 
not be breast feeding (breast feeding must be discontinued in order to 
participate in this study), 
(c) 
have a negative pregnancy test prior to the start of dosing if they are of child-
bearing potential, 
(d) 
or must have evidence of non-child-bearing potential by fulfilling one of the 
following criteria at screening: 
(i) 
Post-menopausal defined as aged more than 50 years and amenorrhoeic 
for at least 12 months following cessation of all exogenous hormonal 
treatments. 
(ii) Women under 50 years old will be considered postmenopausal if they 
have been amenorrheic for at least 12 months following cessation of 
exogenous hormonal treatments, and with LH and FSH levels in the post-
menopausal range for the institution. 
(iii) Documentation of irreversible surgical sterilisation by hysterectomy 
and/orbilateral oophorectomy and/or bilateral salpingectomy but not tubal 
ligation. 
13. 
Male patients with sexual partners who are pregnant or who could become pregnant 
(ie, women of child-bearing potential) must agree to use acceptable methods of 
contraception until 12 weeks after completing study therapy, or longer if required 
for standard RAI administration restrictions and in accordance with local labels, to 
avoid pregnancy and/or potential adverse effects. 
14. 
Adequate organ function as defined by following lab values before randomization: 
(a) 
ANC  1.5 x 109/L (1500 per mm3) 
(b) 
Platelets  100 x 109/L (100,000 per mm3) 
(c) 
Hemoglobin  9 g/dL 
(d) 
ALT/SGOT and AST/SGPT < 2.5 X upper limit of normal (ULN). 
(e) 
Bilirubin  1.5 X ULN (with the exception that patients with elevated 
unconjugated bilirubin due to a pre-existing diagnosis of Gilbert’s syndrome 
are eligible for the study) 
(f) 
Serum creatinine clearance > 50mL/min by either Cockcroft-Gault formula 
(see Appendix E) or 24hr urine collection analysis. 
15. 
Patients must be able to swallow selumetinib/placebo capsules for the duration of 
the study treatment period. This may exclude some patients with swallowing 


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dysfunction due to the specific technique required for their thyroid surgery. 
Functional assessment of swallowing ability may be made by the treating 
Investigator. 
4.1.1 
Genetics research study (optional blood sample) 
1. 
For inclusion in the optional genetics research study patients must provide optional 
genetics research informed consent. 
2. 
If a patient declines to participate in the genetics research, there will be no penalty 
or loss of benefit to the patient.  A patient who declines genetics research 
participation will not be excluded from any other aspect of the main study. 
4.1.2 
Biomarkers research study on tumour progression biopsy 
For inclusion in the optional progression tumour sample study, patients must provide optional 
consent for this sample to be obtained. 
If a patient declines to provide consent to obtain optional tumour sample on progression, there 
will be no penalty or loss of benefit to the patient, and the patient will not be excluded from 
any other aspect of the main study. 
4.2 
Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
1. 
Known distant metastatic disease at study entry. Investigators are not required to 
specifically screen patients for distant metastasis beyond their normal Standard of 
Care practices and the protocol-specific post-operative imaging assessments, but 
any patient with known distant metastatic disease at screening must be excluded. 
2. 
Diagnosis of anaplastic thyroid cancer, medullary thyroid cancer, or Hürthle cell 
carcinoma (refer to inclusion criterion 4 for further details on Hürthle cell 
eligibility). 
3. 
Presence of anti-Tg antibodies at screening (as determined by standardised central 
methodology, refer to Section 6.4.3.4). 
4. 
Previous treatment with 131I (RAI) at any time in the past or external beam radiation 
therapy (EBRT) within 6 months before randomization. 
5. 
Any unresolved toxicity  CTCAE Grade 2 from previous anti-cancer therapy 
including the patient’s recent thyroid cancer surgery. 
6. 
Having received an investigational drug during the last 4 weeks prior to first dose of 
study treatment. 


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7. 
Receiving herbal supplements or medications known to be strong inhibitors or 
inducers of the CYP1A2, CYP2C19 and CYP3A4 enzymes unless such products 
can be safely discontinued at least 14 days before the first dose of study medication. 
8. 
Recombinant human TSH (rhTSH, Thyrogen):  
(a) 
Patients with known hypersensitivity to rhTSH will be excluded. 
(b) 
Patients not willing to use rhTSH prior to their RAI treatment will also be 
excluded (ie, patients or clinicians choosing withdrawal of thyroid hormone 
treatment prior to their RAI treatment will be ineligible for this study). 
9. 
Patients requiring medication with high content in iodide (amiodarone), or patients 
receiving IV iodine containing contrast as part of radiographic procedure within the 
last 3 months prior to the planned RAI treatment (unless a urine measurement 
demonstrates that urinary iodide level has returned to normal range earlier than 3 
months following administration of a contrast agent). 
10. 
Patients with clinically significant cardiovascular disease as defined by the 
following:  
(a) 
Uncontrolled hypertension (at randomization: BP 150/95 despite optimal 
therapy) 
(b) 
LVEF < 55% measured by echocardiography (or MUGA) 
(c) 
Symptomatic heart failure (NYHA grade II-IV), prior or current 
cardiomyopathy, or severe valvular heart disease 
(d) 
Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite 
medical therapy) 
(e) 
Atrial fibrillation with a ventricular rate >100 bpm on ECG at rest 
(f) 
Acute coronary syndrome within 6 months prior to starting treatment 
(g) 
Mean QTc interval >470 ms  
11. 
Patients with the following ophthalmological findings/conditions: 
(a) 
Intraocular pressure >21 mmHg, or uncontrolled glaucoma (irrespective of 
intraocular pressure) 
(b) 
Current or past history of central serous retinopathy or retinal vein occlusion 
12. 
Patients with a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to agents used in the study. 


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13. 
Any evidence of severe or uncontrolled systemic disease, active infection, active 
bleeding diatheses or renal transplant, including any patient known to have hepatitis 
B, hepatitis C or human immunodeficiency virus (HIV). 
14. 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection or psychiatric illness/social situations that would limit compliance with 
study requirements. 
15. 
Pregnant women will be ineligible (breast feeding should be discontinued if the 
mother is treated with study therapy). 
16. 
Male or female patients of reproductive potential who are not employing an 
effective method of contraception (refer to Section 5.1.2). 
17. 
Refractory nausea and vomiting, chronic gastrointestinal diseases, or significant 
bowel resection that in the Investigator’s opinion would preclude adequate 
absorption of study therapy. 
18. 
History of another primary malignancy within 5 years prior to starting study 
treatment, except for adequately treated basal or squamous cell carcinoma of the 
skin or cancer of the cervix in situ and the disease under study.  
19. 
Clinical judgement by the investigator that the patient should not participate in the 
study. 
20. 
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site). 
21. 
Previous treatment with any MEK or BRAF inhibitor. 
22. 
Previous treatment in the present study. 
4.2.1 
Genetics research study (optional blood sample) 
1. 
Exclusion criteria for participation in the optional genetics research component of 
the study: 
(a) 
Previous allogeneic bone marrow transplant 
(b) 
Whole blood transfusion within 120 days of the date of genetic sample collection 
(except for leukocyte depleted blood transfusion, which is allowed) 
For procedures for withdrawal of incorrectly enrolled patients see Section 5.3. 


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5. 
STUDY CONDUCT 
5.1 
Restrictions during the study 
5.1.1 
Low-iodine diet 
Published data and opinion regarding the necessity for a low iodine diet prior to RAI therapy 
or a diagnostic whole body scan is variable.  For the purpose of this study a low iodine diet 
will be mandated in order to standardise patient care and study data as best as possible. 
Compliance to the low iodine diet will not be recorded or assessed, and all randomised 
patients will receive RAI treatment as planned. Refer to Table 2 and the Study Plan (Table 3) 
for further details. An example low iodine diet is provided as Appendix F to this protocol. 
A low iodine diet is necessary at two occasions in the study: 
Prior to RAI adjuvant treatment 
All patients must be willing to adhere to the low iodine diet for a period of 1 week before their 
planned RAI adjuvant treatment, until the day after their RAI therapy. 
Prior to the primary endpoint Stage 2 assessments 
All patients must be willing to adhere to the low iodine diet for a period of 1 week before the 
diagnostic 131I dose used prior to the primary endpoint WBS assessment (131I nuclear medicine 
scan), until the diagnostic WBS assessment is completed. This is only relevant for patients 
who pass Stage 1 primary endpoint assessments (refer to Section 6.4.2). 
5.1.2 
Other study restrictions 
The following restrictions also apply while the patient is receiving selumetinib or placebo:  
1. 
Female patients of child-bearing potential will be required to use reliable methods 
of contraception until 4 weeks after the last dose of selumetinib/placebo or longer if 
required for standard RAI administration restrictions and in accordance with local 
labels.  Male patients will be required to use reliable methods of contraception until 
12 weeks after the last dose of the last study treatment, or longer if required for 
standard RAI administration restrictions and in accordance with local labels.  
Reliable methods of contraception should be used consistently and correctly.  
Acceptable methods include implants, injectables, combined oral contraceptives 
(which must all be combined with barrier methods of contraception), some IUDs 
and vasectomised partner.  Sexual abstinence is also an acceptable method of 
contraception according to ICHM3. 
2. 
Fasting restrictions for the study are described in Section 5.5.2.   
3. 
Patients should avoid excessive sun exposure and use adequate sunscreen protection 
if sun exposure is anticipated. 


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4. 
Patients should avoid large amounts of grapefruit and Seville oranges (and other 
products containing these fruits eg, grapefruit juice or marmalade) during the study 
treatment period. 
5. 
Selumetinib/placebo capsules contain vitamin E in form of D-Į-tocopheryl 
polyethlen glycol 1000 succinate (TPGS), a water-soluble form of vitamin E which 
acts as a formulation excipient. The maximum daily dose of vitamin E that a study 
subject may receive from selumetinib /placebo is approximately 261.6 mg/day. 
Therefore: 
x Patients should not take any supplemental vitamin E.  High doses of vitamin E 
have been reported to cause bleeding and interrupt blood coagulation processes. 
x Selumetininb/placebo 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 anticoagulant should be adjusted 
accordingly. 
6. 
Permitted and excluded antiemetic medications in this study are described in 
Section 5.6.   
7. 
Permitted and excluded medications for management of skin toxicities (eg, rash) are 
described in Appendix G: “Guidance for Management of Adverse Events in Studies 
of Selumetinib.” All patients will be given prophylactic provision of emollient 
cream to take home and to start using when starting study treatment. 
8. 
Unless patients require re-treatment, they should not be enrolled in other studies 
evaluating novel therapies for thyroid cancer for the entire study duration. 
5.2 
Patient enrolment, randomisation and initiation of investigational 
product 
The Principal Investigator or delegate will: 
1. 
Obtain signed informed consent from the potential patient before any study specific 
procedures are performed. 
2. 
Determine patient eligibility. See Sections 4.1 and 4.2 
3. 
Call IVRS/IWRS to assign the eligible patient a unique enrolment number 
(beginning with ‘E#’), and randomisation code (subject number).  Randomisation 
codes will start at 001 and go up. 
Randomisation codes will be assigned strictly sequentially by IVRS/IWRS as patients are 
eligible for randomisation.  


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If a patient withdraws from the study, then his/her enrolment/randomisation code cannot be 
reused. 
If a patient withdraws from the study, after they have received study treatment then they 
cannot re-enter the study. 
If a patient is re-screened, a new E-code will always be assigned. 
5.2.1 
Procedures for randomisation 
Patients who satisfy all the entry criteria will be centrally assigned by the IVRS/IWRS, 
according to the randomisation scheme generated by the Biostatistics Group, AstraZeneca, to 
selumetinib or placebo in a ratio of 2:1.  
Every effort should be made to minimise the time between randomisation and starting 
treatment.  Patients must not be randomised unless all eligibility criteria have been met. 
IVRS/IWRS will be used for allocation of enrolment number, allocation of randomisation 
number, study medication assignment, discontinuation from study treatment, emergency code 
breaks and study drug shipment confirmation.   
5.3 
Procedures for handling patients incorrectly enrolled, randomised 
or initiated on investigational product 
Patients who fail to meet the inclusion/exclusion criteria should not, under any circumstances, 
be enrolled or receive study medication.  There can be no exceptions to this rule.  
Where patients that do not meet the study criteria are enrolled in error, incorrectly randomised 
a discussion must occur between AstraZeneca Study Physician and the Investigator regarding 
the patient’s safety and well-being and whether to continue or discontinue the patient from the 
study treatment. The AstraZeneca Study Physician is to ensure all such decisions are 
appropriately documented. In situations where an agreement cannot be reached, the patient 
should have their therapy stopped, then followed up for the primary endpoint assessments and 
safety. Those patient randomised in error should remain in the study and be followed for the 
primary endpoint assessments and safety where possible.  
5.4 
Blinding and procedures for unblinding the study  
5.4.1 
Methods for ensuring blinding 
The active and placebo capsules will appear identical and presented in the same packaging to 
ensure blinding of the medication.  Medication will be labelled using a unique material pack 
code which is linked to the randomisation scheme.  IVRS/IWRS will allocate randomisation 
numbers sequentially when sites call IVRS/IWRS to randomise an eligible patient.  
IVRS/IWRS will allocate the medication pack code to be dispensed to the patient. 
All patients must remain blinded until after the 18 month primary endpoint data analysis has 
been conducted for the study; most patients will thus remain blinded for longer periods of time 
than their initial 18 month follow up period.  Any patient that is re-treated prior to the 18 


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month primary endpoint time-point (refer to guidelines in Section 5.9), must not be unblinded 
until after the primary analysis of 18 month primary endpoint data from all patients in the 
study. 
The personnel analyzing the PK samples will be unblinded to treatment allocation in order to 
organise the appropriate sample analysis. The treatment allocation information will be kept in 
a secure location until the end of the study. 
Once the 18 month primary endpoint data analysis has been conducted for the study, patients 
may be unblinded for the remaining study follow up. 
5.4.2 
Methods for unblinding the study 
Individual treatment codes, indicating the treatment randomisation for each randomised 
patient, will be available to the investigator(s) or pharmacists from the IVRS/IWRS.  
Procedures for emergency unblinding will be described in the IVRS/IWRS user manual that 
will be provided to each centre. 
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomisation. The 
investigator documents and reports the action to AstraZeneca, without revealing the treatment 
given to patient to the AstraZeneca staff. 
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational product and that potentially require 
expedited reporting to regulatory authorities.  Treatment codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each individual 
patient have been made and documented. 
5.5 
Treatments 
5.5.1 
Identity of investigational product(s) 
Investigational product 
Dosage form and strength 
Manufacturer 
Selumetinib 
 
25 mg Hyd-Sulfate capsule 
AstraZeneca 
Placebo to match selumetinib 
Capsule  
AstraZeneca 
 
5.5.2 
Doses and treatment regimens 
Patients will be randomised on a 2:1 basis, via IVRS/IWRS, to receive either selumetinib 
75 mg twice daily, or matching placebo. 
Patients will be instructed to take 3 capsules orally on an empty stomach (no food or drink 
other than water for 2 hours prior to dosing and 1 hour after dosing), twice a day 
approximately 12 hours apart according to the Study Plan.  Capsules should be taken with 


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water only.  On clinic days when PK samples are scheduled to be taken, dosing should be 
delayed until arrival at the clinic and until the pre-dose PK sample has been taken.  
Selumetinib/placebo will be supplied in bottles of 60 capsules of 25 mg strength. At 
Randomization visit, selumetinib/placebo for the entire treatment period will be dispensed (5 
bottles). Individual bottles will be dispensed in accordance with the medication identification 
numbers provided by the IVRS/IWRS. 
Day 1 of study treatment must occur within 16 weeks of the patient’s thyroid cancer surgery 
(their last surgery if it was a 2-stage thyroidectomy).   
5.5.3 
Management of study treatment related toxicity 
The immediate management of any adverse event should be according to standard clinical 
practice for that event. Subsequent management of treatment related adverse events should be 
guided by the Investigators’ assessment of causality. 
5.5.3.1 
Selumetinib dose interruption or reduction 
Patients should remain on study treatment continuously for a minimum of 7 consecutive days 
prior to their planned RAI therapy, on the day of RAI therapy, and for 5 consecutive days 
afterwards. If necessary, RAI therapy may be postponed up to 1 week at the discretion of the 
Investigator to allow the patient receive study treatment for a minimum of 7 consecutive days 
(as long as the total duration of study treatment does not exceed 43 days) 
For all adverse events reported in this study that are considered at least partly causal to 
administration of selumetinib, the following dose modification guidance should be applied.   
Study treatment with selumetinib/placebo should be temporarily interrupted if one of the 
following AEs are observed (and considered causal to study treatment), despite optimal 
supportive care (ie, supportive treatment may be given prior to withholding study treatment): 
x
Any intolerable adverse event regardless of Grade 
x
Any adverse events  CTCAE Grade 3 
On improvement of the adverse event to Grade 1 (Grade 2 for rash) or baseline, study 
treatment may be restarted at the original dose or may be reduced at the discretion of the 
investigator. One dose reduction of study treatment to 50 mg twice daily is permitted before 
permanent discontinuation.   
x
If a further episode of the same AE subsequently requires dose interruption, 
selumetinib may be restarted at the next dose level down on improvement of the 
AE. 
x
If a different AE subsequently requires dose interruption, selumetinib may be 
restarted at the same dose or at the next dose level down on improvement of the AE.   


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x
Selumetinib should not be re-escalated to an earlier dose level on improvement of 
an AE.  
x
The schedule of assessments described in Table 3 should continue relative to Day 1 
in the event of selumetinib dose interruption or reduction. 
Therefore, the dose reduction/adjustment algorithm in the study allows for 2 steps only:  
75 mg twice daily (initial dose) 
Ļ 
50 mg twice daily 
Ļ 
permanent discontinuation 
If a patient suspends study treatment (selumetinib or placebo) for more than 14 days they are 
no longer eligible to re-start the study treatment. 
All dose delays, reductions and adjustments will be recorded in the appropriate electronic 
Case Report Form (eCRF). 
The guidance above should also be followed for dose interruptions or reductions for adverse 
events of rashes or diarrhoea. Guidance for interruption or reduction of treatment with 
selumetinib may be considered for particular events, as indicated in the algorithms provided as 
a separate study aid in the “Guidance for Management of Specific Adverse Events in Studies 
of Selumetinib” (refer to Section 5.5.3.2).   
5.5.3.2 
Management and investigation of specific selumetinib related AEs 
Recommendations for the management or investigation of the following specific AEs is 
provided in Appendix G: Guidance for Management of Adverse Events in Studies of 
Selumetinib. 
x
Rash: early initiation of treatment for rash is strongly recommended to minimise the 
duration and severity of the adverse event. All patients should be given prophylactic 
provision of emollient cream to take home and to start using when starting study 
treatment as indicated in the algorithm for management and investigation of rash 
included in Appendix G. 
x
Visual disturbances: symptoms, including blurred vision, have been reported during 
treatment with selumetinib. Events consistent with central serous retinopathy have 
been reported in a small number of patients receiving treatment with selumetinib, 
generally in combination with other novel targeted anti-cancer agents. AEs of 
central serous retinopathy and retinal vein occlusion have been reported in studies 
of other MEK inhibitors (Lemech & Arkenau 2012). Investigation to determine the 
underlying cause of visual disturbance is recommended. 


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x
Diarrhoea: early initiation of treatment for diarrhoea is strongly recommended to 
minimise the duration and severity of the adverse event. Treatment provision will 
be according to Investigator discretion according to local practice and regulations.  
x
Dyspnoea: new or worsening dyspnoea has been reported during treatment with 
selumetinib; investigation to determine the underlying cause is recommended. 
5.5.4 
Additional study drugs 
5.5.4.1 
Thyrogen (rhTSH, thyrotropin alfa for injection) 
Thyrogen use prior to the RAI ablative dose 
Effective use of RAI therapy requires stimulation by TSH in order to maximise RAI uptake by 
thyroid cells. Recombinant human TSH (rhTSH or Thyrogen) will be used to stimulate iodide 
uptake according to the manufacturer’s recommendation (0.9 mg intra-muscular injection for 
2 days immediately prior to the RAI treatment according to the Study Plan Table 3). rhTSH is 
approved for use in routine clinical care as a diagnostic tool to stimulated serum thyroglobulin 
and RAI uptake for diagnostic scanning and as an adjunct to RAI ablation in many countries. 
This allows patients to avoid the hypothyroidism state, since they can maintain their routine 
thyroid hormone supplementation. Patients or clinicians choosing withdrawal of thyroid 
hormone treatment for this purpose will be ineligible for this study. All randomised study 
patients will receive Thyrogen twice prior to their RAI treatment dose. 
Thyrogen use for the primary endpoint assessments (18 months post-RAI) 
For those patients that progress to Stage 2 of the primary endpoint assessments (refer to 
Section 6.4.2),  Thyrogen will be used to stimulate iodide uptake immediately prior to 
administering the diagnostic 131I dose for the primary endpoint WBS assessment.  Patients will 
receive a 0.9 mg intra-muscular Thyrogen injection for two consecutive days.  Refer to 
Section 6.4.2.2 for further details. 
5.5.4.2 
Radioactive iodine (RAI) 
All RAI for the study will be locally provided at each site. 
Therapeutic RAI dose (131I) 
A single oral RAI dose of 100 mCi (3.7 GBq) 131I (+/- 10% at the time of administration) will 
be administered to all patients according to the Study Plan Table 3, according to standard 
practice at each site. 
Diagnostic WBS dose (131I) 
For those patients that progress to Stage 2 of the primary endpoint assessments (refer to 
Section 6.4.2),  a single oral RAI dose of 5 mCi (185 MBq) 131I (+/- 10% at the time of 
administration) will be administered for the primary endpoint WBS (nuclear medicine scan) 
18 months following the ablative treatment dose of RAI. Refer to the Study Plan Table 3, and 
Section 6.4.4.2 for further details. 


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5.5.4.3 
Thyroid hormone supplementation (TSH suppression) 
Routine thyroid hormone supplementation (levothyroxine, LT4) is required during the study 
as per standard clinical practice. The purpose of this is both to correct resulting 
hypothyroidism using a dosage appropriate to achieve normal blood levels of thyroid 
hormone, and to inhibit TSH-dependant growth of residual thyroid cancer cells. Thyroid 
hormone supplementation will be adjusted in individual patients with the aim of achieving 
suppressed TSH levels of <0.5 mIU/L for the duration of the study. 
5.5.5 
Study drug labelling 
Each bottle of selumetinib and matching placebo capsules will be labelled by Pharmaceutical 
Development Supply Chain, AstraZeneca or its designee. 
All labels will comply with good manufacturing practice (GMP) regulations, and will state 
that the drug is for clinical use only or that it is the investigational drug and is to be used by 
qualified investigators only and should be kept out of reach of children. The labels will have 
blank spaces for the site personnel to complete the following at the time of drug dispensing: 
enrolment code, visit number and dispensing date.  
Label text will be translated into local language. 
Each bottle of selumetinib/placebo capsules will have a tear-off portion that will be removed 
at the time of dispensing and attached to the Drug Label Accountability Log.  
5.5.6 
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions.  The 
investigational product label on the bottle specifies the appropriate storage. 
5.6 
Concomitant medications 
The use of antiemetic medication for the prevention of nausea caused by administration of 
radioactive iodine is permitted in this study according to local clinical practice (with the 
exception of aprepitant which is an excluded medication in this study, due to the potential for 
modification of selumetinib exposure via CYP3A4). The administration of any antiemetic 
medication must be recorded in the appropriate sections of the Case Report Form. 
All patients will be given prophylactic provision of emollient cream to take home and to start 
using when starting study treatment as indicated in the algorithm for management and 
investigation of rash included in Appendix G: “Guidance for Management of Adverse Events 
in Studies of Selumetinib.” 
The following treatments/drugs are restricted in this study: 
x
No other anti-cancer agents, or investigational drugs should be administered whilst 
patients are receiving study medication or are in follow-up in this study (unless the 
patient withdraws from the study, or meets the re-treatment criteria in Section 5.9).   


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x
Patients who are taking coumarin anticoagulants should increase the frequency of 
assessment of anticoagulation, such as INR measurements, during the study 
treatment period with selumetinib/placebo.   
x
The maximum dose of vitamin E patients may receive from selumetinib is 
approximately 261.6 mg/day. The concomitant intake of excessive 
(supratherapeutic) doses of vitamin E should be avoided in patients receiving the 
capsule formulation. 
x
Throughout the study, patients should avoid changes to, or the addition of all other 
concomitant medications, in particular any that may affect the metabolism of 
selumetinib (eg, CYP1A2 or 3A4 inhibitors/inducers), unless considered clinically 
indicated. 
Other medication, which is considered necessary for the patient’s safety and well being, may 
be given at the discretion of the investigator and recorded in the appropriate sections of the 
Case Report Form.  
All concomitant medications will be recorded on the CRF until 30 days after the last dose of 
study treatment, and after this time a study-specific record must be kept of any further 
treatment for thyroid cancer (including surgery), or treatment for RAI-related AEs/SAEs until 
the last study visit for all patients (refer to Section 5.9). 
5.7 
Treatment compliance 
The administration of all study drugs (including investigational products) should be recorded 
in the appropriate sections of the Case Report Form. 
5.7.1 
Accountability 
The study drug provided for this study will be used only as directed in the study protocol. 
The study personnel will account for all study drugs dispensed to and returned from the 
patient. 
Where appropriate facilities and procedures for drug destruction exist, and prior approval from 
the site monitor has been received, site personnel will account for all unused drugs and for 
appropriate destruction. 
Where such facilities do not exist study site personnel/study monitor will return all unused 
drugs to AstraZeneca or its designee according to country rules. 
The AstraZeneca monitors will ensure that all drug-handling procedures at sites are 
appropriate, and that all certificates of delivery and return are completed and signed by the 
site, AstraZeneca, or its delegate, as appropriate.  In addition, the monitor will check that the 
certificate of destruction has been signed by the site, if study drug destruction is performed at 
the site. 


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Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
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5.8 
Discontinuation of investigational product 
Patients may be discontinued from investigational product (IP) in the following situations: 
x
Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment 
x
Adverse Event 
x
Risk to patients as judged by the investigator and/or AstraZeneca 
x
Severe non-compliance to protocol as judged by the investigator and/or 
AstraZeneca 
x
A female patient becoming pregnant 
5.8.1 
Procedures for premature discontinuation of a patient from investigational 
product  
A patient that decides to prematurely discontinue investigational product will always be asked 
about the reason(s) and the presence of any adverse events.  If possible, they will be seen and 
assessed by an investigator(s).  Adverse events will be followed up (See Sections 6.5.3 and 
6.5.4), and all study drugs should be returned by the patient.  In this situation, a treatment 
discontinuation visit will be conducted as soon as possible after the patient received the last 
dose of study drug (selumetinb/placebo). A single 12-lead ECG, physical examination, vital 
signs measurement, clinical chemistry, haematology is also required at premature 
discontinuation of treatment. As long as the patient does not withdraw consent, study visits 
will be continued according to study plan. RAI treatment will be administered as soon as 
possible after last dose of investigational product and WBS will be performed 3-10 days 
following the RAI dose. 
RAI treatment must be preceded by 0.9 mg intra-muscular injection of thyrogen administered 
2 days immediately prior to RAI. 
30 days post treatment visit will be conducted 30 days (+/- 2days) after last dose of 
investigational product or RAI (whatever latest). The schedule of follow – up assessments 
described in Table 3 should continue relative to RAI treatment in the event of selumetinib 
premature discontinuation. 
A patient that decides to prematurely discontinue investigational product and has not received 
RAI treatment should continue study visits according to study plan. The schedule of follow – 
up assessments described in Table 3 should continue relative to planned date of RAI 
treatment. 
If a patient is withdrawn from the study (ie, withdraws consent for follow-up procedures), see 
Section 5.10. 


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Edition Number 4 
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Any patient with an AST, ALT or bilirubin value above ULN at time of the last dose of 
selumetinib/placebo should have a further liver chemistry profile (AST, ALT, bilirubin and 
ALP) performed 30 days (±7days) after discontinuation. 
5.9 
Criteria for further thyroid cancer therapy during the study 
5.9.1 
Re-treatment prior to the 18 month primary endpoint assessments 
It is acknowledged that there is variability in thyroid cancer re-treatment clinical practice.  The 
study-specific criteria below are designed to standardise re-treatment prior to the primary 
endpoint assessments for the purpose of this study as best as possible. Thus, further thyroid 
cancer therapy (eg, additional surgery or RAI treatment) prior to the primary analysis of 
complete remission at 18 months post-RAI, must not be administered unless any of the 
following criteria are met.  
Patients meeting the following re-treatment criteria do not have to be re-treated, they can 
instead be followed expectantly without re-treatment at the discretion of the treating 
Investigator. 
5.9.1.1 
Biochemical disease re-treatment criteria 
The first scheduled post-RAI follow up for serum Tg will be assessed 9 months after the RAI 
dose (± 3 months). Tg assessment for this purpose may take place at any time from 6 months 
after the patient’s RAI treatment (but not before 6 months).   
All biochemical sample analysis for study re-treatment criteria must be performed by 
standardised central laboratory methodology (for further details refer to the Laboratory 
Manual). 
Patients must not be re-treated for thyroid cancer unless any of the following biochemical 
criteria are met: 
1. 
If a serum Tg level  5 ng/mL on central analysis is measured during TSH 
suppression, then a repeat Tg sample must be assessed by central analysis 2-4 
weeks later. The patient must not be re-treated unless both centrally analysed 
samples demonstrate the suppressed Tg level to be 5 ng/mL or higher.   
2. 
If a serum Tg level  10 ng/mL is measured following TSH stimulation, the 
patient may be re-treated (a repeat sample for confirmation is not necessary). Note, 
a stimulated Tg assessment is not part of the study-specific follow up plan for 
patients prior to the 18 month primary endpoint assessments (thus it is not 
recommended or required, and is not included in the Study Plan). However, if a 
stimulated Tg assessment is performed due to local practice, this re-treatment 
criterion applies.  
3. 
If an increase (delta change) in serum Tg level of 3 ng/mL or more is determined 
between two Tg assessments taken 2-4 weeks apart (due to a repeat sample), the 
patient may be re-treated.  


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Edition Number 4 
Date 01 July 2014 
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Thus, in the absence of structurally identifiable disease, patients in this study should have 
continued observation without additional thyroid cancer treatment (eg, additional RAI, 
surgery) until the study primary endpoint (18 months after RAI treatment), if the serum Tg 
level remains below 5 ng/mL during TSH suppression, below 10 ng/mL following TSH 
stimulation (if assessed), and is either stable/declining, or rising less than 3 ng/mL between 
samples 2-4 weeks apart.   
Note: If a patient has Tg levels below the above re-treatment criteria, but TgAb are detected 
(ie, the patient is TgAb positive; refer to Section 6.4.3.4), the patient should not be re-treated 
unless new structural disease is detected according to Section 5.9.1.2 (ie, it is recommended 
that patients are not re-treated on the basis of new antibodies alone, in the absence of 
structural disease).  
Unscheduled samples and local analysis 
It is acknowledged that Investigators may wish to also perform their own local biochemical 
analysis according to local standard of care. In general, unscheduled samples that are taken 
either outside of the visit window specified, or in addition to the scheduled study samples, 
should not be sent for standardised central analysis. Only if such unscheduled local analysis 
leads the Investigator to wish to administer further therapy for thyroid cancer, should a sample 
ideally be sent for central analysis and the above criteria applied before the patient is re-
treated.   
5.9.1.2 
Structural disease re-treatment criteria 
The first post-RAI ultrasound follow up will be assessed 9 months after the RAI dose (± 3 
months). Ultrasound assessment for this purpose may take place at any time from 6 months 
after the patient’s RAI treatment (but not before 6 months).  
Patients must not be re-treated for thyroid cancer unless any of the following structural criteria 
are met: 
1. 
In the absence of any biochemical evidence of thyroid cancer, structural DTC 
should be confirmed prior to re-treatment, by positive histology/cytology from a 
biopsy/FNA of ultrasonographically suspicious lesions or lymph nodes  5 mm in 
the smallest diameter (refer to Section 6.4.4.5).  
2. 
Identification of new distant metastases (these do not need to be confirmed by 
biopsy). Assessment of potential distant metastases is not required, but may be 
performed if clinically indicated at the discretion of the treating Investigator. 
5.9.1.3 
Patient management on study (up to the primary analysis at 18 months post-
RAI) 
At the required follow up visits, the following questions should be answered for each subject: 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
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1. 
Does the patient have a suppressed Tg  5 ng/mL, a TSH stimulated Tg  10 ng/mL 
or a rising Tg level (increase of 3 ng/mL or more) according to the guidelines in 
Section 5.9.1.1? 
2. 
Does the patient have new loco-regional structural thyroid cancer according to the 
guidelines in Section 5.9.1.2? 
3. 
Does the patient have new distant metastatic lesions according to the guidelines in 
Section 5.9.1.2? 
If the answer is yes to any of the questions, the patient is unlikely to enter remission and may 
be re-treated for thyroid cancer (but does not have to be).  
Full details of any thyroid cancer re-treatment must be recorded on the appropriate eCRF. 
Any re-treated patients will remain in the study and should enter standard of care follow up 
according to local practice until 3 years after their initial RAI therapy (refer to Section 6.4.8).  
Patients who are re-treated prior to the primary endpoint at 18 months post-RAI do not require 
primary endpoint disease assessments performing, however these patients should continue to 
follow all protocol-scheduled visits for safety (AE/SAE follow-up) as described in the Study 
Plan Table 3 and in Section 6.5.  Patients do not need to attend these follow up visits in person 
(telephone contact is permitted), however when local follow-up visits coincide with protocol-
specified visits, these should ideally be in person where possible. 
If the answer is no to all questions, the patient should continue the study follow-up as per 
protocol without additional thyroid cancer re-treatment. 
5.9.2 
Re-treatment after the 18 month primary endpoint assessments 
Following completion of all assessments for complete remission at the primary endpoint 
18 months post-RAI, patients may receive re-treatment for thyroid cancer as per clinically 
indicated according to local standard of care.  Any re-treated patients will remain in the study 
and should enter standard of care follow up according to local practice until 3 years after their 
initial RAI therapy (refer to Section 6.4.8). 
Full details of any thyroid cancer re-treatment must be recorded on the appropriate eCRF. 
5.10 
Withdrawal from study 
Patients are at any time free to withdraw from study (investigational product and follow-up 
assessments), without prejudice to further treatment (withdrawal of consent).  Such patients 
will always be asked about the reason(s) and the presence of any adverse events.  If possible, 
they will be seen and assessed by an investigator.  Adverse events will be followed up (see 
Sections 6.5.3 and 6.5.4); any remaining study drug should be returned by the patient. 
5.11 
Replacement of patients 
There will be no replacement of randomised patients in this study for any reason. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
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6. 
COLLECTION OF STUDY VARIABLES 
6.1 
Recording of data 
A Web Based Data Capture (WBDC) system will be used for data collection and query 
handling.  The investigator will ensure that data are recorded on the electronic Case Report 
Forms as specified in the study protocol and in accordance with the instructions provided. 
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed electronic Case Report Forms.  A copy of the completed 
electronic Case Report Forms will be archived at the study site. 
6.2 
Data collection at enrolment 
The following data will be collected & procedures performed for each patient: 
1. 
Informed consent (to include consent for archival tumour sample provision) 
2. 
Demography (date of birth, sex, race) 
3. 
Histological/cytological confirmation of thyroid cancer, including post-operative 
disease staging 
4. 
Medical and surgical history  
5. 
Concomitant medications and previous anti-cancer therapy 
6. 
Assessment of WHO or ECOG performance status (refer to Section 6.2.1) 
7. 
Collection of AEs will start after signing the consent form 
8. 
Physical examination  
9. 
Vital signs (resting blood pressure (BP), pulse rate), weight and height 
10. 
Single ECG 
11. 
Blood samples for clinical chemistry and haematology 
12. 
Blood sample for determination of interfering Tg antibodies (central standardised 
analysis) 
13. 
Local derived BRAF and/or NRAS mutation status (where available) 
14. 
Urinalysis (at sites where the local laboratory is able to determine the required 
parameters, see Section 6.5.5) 


Clinical Study Protocol 
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Edition Number 4 
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15. 
Pregnancy test for female pre-menopausal patients  
16. 
Full ophthalmologic examination, including slit-lamp fundoscopy and intraocular 
pressure examination  
17. 
ECHO or MUGA  
18. 
The following imaging assessments must be performed within the 28 day screening 
period but only after all other screening procedures have confirmed eligibility status 
(refer to Section 6.3): 
(a) 
Neck ultrasound (US) 
(b) 
Neck MRI with contrast 
(c) 
Chest CT scan without contrast 
19. 
Overall assessment of patient eligibility for the study 
20. 
Upon confirmation of patients’ eligibility, patients will be invited to attend the 
randomisation visit.  Patients must not be randomised unless all eligibility criteria 
have been met. 
21. 
Call interactive voice response system (IVRS)/interactive web response system 
(IWRS) to randomise the patient 
6.2.1 
Performance status definitions 
Performance status will be assessed at screening according to either the WHO or ECOG 
criteria as follows: 
0 = Fully active, able to carry out all pre-disease performance/activities without restrictions 
1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature e.g., light housework, office work 
2 = Ambulatory and capable of self-care, but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 = Completely disabled, cannot carry on self-care, totally confined to bed or chair. 
6.3 
Post-operative imaging assessments for eligibility 
The post-operative imaging assessments of US, neck MRI and chest CT are performed during 
screening to determine study eligibility. These assessments must determine the absence of 
macroscopic persistent disease post-surgery for a patient to be eligible prior to randomisation. 


Clinical Study Protocol 
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Edition Number 4 
Date 01 July 2014 
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The post-operative imaging assessments must be scheduled once all other screening 
assessments and eligibility criteria have been verified. 
The screening chest CT procedure must be performed without iodine containing contrast 
agent.  
Eligibility will be determined by the local investigational site. 
Acquisition guidelines for the post-operative imaging assessments will be provided separately 
to this protocol. 
In addition to information recorded on the eCRF for US, the post-operative images for chest 
CT and neck MRI must be collected and sent to the central imaging CRO. 
6.4 
Efficacy  
6.4.1 
Complete remission  
The primary endpoint for this study is complete remission rate at 18 months (following RAI 
treatment). 
Definition of complete remission: 
Patients will be defined to be in complete remission if all of the following criteria can be 
demonstrated: 
1. 
Serum Tg levels < 1ng/mL during rhTSH stimulation, in the absence of interfering 
Tg antibodies, as assessed by standardised central laboratory analysis. 
2. 
No confirmed evidence of thyroid cancera on neck US, as assessed by investigator 
site review. 
3. 
No confirmed radiological evidence of thyroid cancera, as assessed by blinded 
independent central review.  
4. 
No histopathological evidence of thyroid cancer on FNA/biopsy when performed, 
as assessed by investigator site review. 
5. 
No further thyroid cancer therapy was administered in the first 18 months following 
the initial RAI treatment. 
There are two main components to complete remission: biochemical remission and structural 
remission. Biochemical remission is measured by Tg and structural remission is assessed by 
the imaging assessments US, MRI, CT and WBS in conjunction with biopsy/FNA.  
A staged approach will be taken for performing assessments contributing to the primary 
endpoint, to avoid unnecessary assessments for individual patients who received further 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
69(120) 
therapy prior to the primary assessment, and for those patients not in biochemical remission 
(as determined by serum Tg levels in the absence of interfering Tg antibodies). 
aConfirmation of evidence of structural DTC will be either histopathological (from a 
biopsy/FNA; as criterion 4 above), or RAI-avid disease (refer to Section 6.4.4.2). In this 
disease setting, structural abnormalities that are not RAI-avid and do not have confirmed 
histopathology consistent with DTC (ie are not biopsy proven) are considered benign in the 
absence of biochemical DTC. 
6.4.2 
Staged approach to primary endpoint assessments 
Full details of the staged approach to the primary endpoint assessments are outlined below.  
There will be 3 stages of assessments. Patients that have been re-treated for thyroid cancer 
will not have any primary endpoint assessments performed. All patients who have not been re-
treated for thyroid cancer will have stage 1 assessments performed. The decision on whether 
to proceed to stage 2 and 3 assessments for patients that have not been re-treated will be based 
on centrally analysed biochemical data (Tg and TgAb data).  
Sites will receive results from standardised central laboratory analysis of the biochemical data 
and make a decision to proceed based on these results. Patients identified as not in 
biochemical remission will not be required to have all imaging assessments described in 
Section 6.4.1 performed. 
For patients that have imaging assessments performed, the appropriate data will be sent to the 
imaging CRO for blinded independent central review to identify presence or absence of 
structural disease. Note: results from the central imaging review will not be reported to 
clinical sites. 
Briefly: 
In stage 1, suppressed Tg will be determined together with neck US assessment for all patients 
who did not require re-treatment for thyroid cancer during the first 18 months of follow up 
(refer to Section 6.4.2.1).  
In stage 2, rhTSH stimulated Tg and diagnostic WBS will be performed (refer to 
Section6.4.2.2). 
In stage 3, additional radiological imaging (chest CT and neck MRI) will be performed (refer 
to Section 6.4.2.3).   
Stage 1 assessments must be started 18 months ± 2 weeks following the patient’s RAI dose, 
and all necessary primary endpoint assessments (all 3 stages if required) must be completed 
within an 8 week period (refer also to Table 4). 
Refer to the flowchart Figure 3 for a visual representation of the staged approach for primary 
endpoint assessments. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
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Refer to Section 6.4.5 for the process of determining complete remission from the primary 
endpoint assessment data. 


Clinical Study Protocol 
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Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
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Figure 3 
Flow chart for staged primary endpoint assessments 
 


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Edition Number 4 
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6.4.2.1 
Primary endpoint assessments Stage 1 
Patients that have been re-treated for thyroid cancer between their initial RAI dose and the 
primary endpoint assessments 18 months later (refer to Section 5.9 for re-treatment criteria), 
will not have any primary endpoint assessments performed. For the purpose of the primary 
endpoint, such re-treated patients will be determined not to be in complete remission. 
In stage 1, all patients that have not previously been re-treated for thyroid cancer will have: 
x
Suppressed Tg level determined by standardised central laboratory analysis.  
x
TSH and TgAb (using the same blood draw for suppressed Tg) determined by 
standardised central laboratory analysis. Refer to Section 6.4.3. 
x
Neck US assessment for structural disease to be assessed by investigator site 
review. Refer to Section 6.4.4.1. 
Suspicious lesions identified by US  5 mm in the shortest diameter should be biopsied or 
aspirated by fine needle. All biopsy/FNA samples will be assessed locally at each site. Lesions 
identified by US < 5 mm in the shortest diameter do not require a biopsy. 
All neck US and biopsy/FNA samples will be assessed locally at each site. The relevant US 
information with any biopsy findings will be provided to the imaging CRO as part of the 
blinded independent central review. 
When to proceed to stage 2 assessments 
All patients in the following situations should proceed to stage 2 assessments: 
1. 
Patients with suppressed Tg < 1 ng/mL. These patients should proceed to stage 2 
regardless of the TgAb or US results. 
2. 
Patients who are TgAb positive in stage 1 (regardless of the suppressed Tg level, 
and US results). 
3. 
Patients who fulfil either of the 2 above criteria, and have a biopsy/FNA result 
pending (ie, Investigators should not wait for the biopsy/FNA result before 
performing stage 2 assessments). 
When not to proceed to stage 2 assessments 
All patients in the following situations will be classified not in complete remission and should 
not proceed to stage 2 assessments: 
1. 
Patients who have suppressed Tg level  1 ng/mL in the absence of TgAb 
(unequivocal biochemical disease). 


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2. 
Patients with a positive biopsy/FNA that confirms the presence of structural DTC. 
Note that if the biopsy/FNA results are not yet available, the patient should not 
delay proceeding to stage 2 assessments. 
Patients who demonstrate presence of disease and do not proceed to stage 2 assessments will 
enter standard of care treatment/follow up at each centre as determined by the treating 
Investigator, and will continue to be followed in this study until 3 years following their 
initial RAI dose (refer to Section 6.4.6). 
6.4.2.2 
Primary endpoint assessments Stage 2 
In stage 2, patients will have: 
x
rhTSH stimulated Tg level determined by standardised central laboratory analysis.  
x
TgAb (from the same blood draw for rhTSH stimulated Tg) determined by 
standardised central laboratory analysis. TSH will not be analysed from this sample. 
A repeat (third) sample for TgAb analysis may be required 10 days ± 3 days later if 
the stage 1 and 2 TgAb status is discordant (refer to Table 5). 
x
Diagnostic nuclear medicine 131I scan (WBS) to be evaluated by blinded 
independent central review. 
These assessments will require the patient to follow a low iodine diet for a period of 1 week 
before the diagnostic 131I dose, until the diagnostic WBS assessment is completed (refer to 
Section 5.1.1 and Appendix F). Patients will also receive two Thyrogen injections (refer to 
Section 5.5.4.1) on consecutive days (day 1 and 2), followed by a diagnostic dose (5 mCi) of 
131I on either day 2 or day 3, and a blood draw for stimulated Tg central assessment and WBS 
both on day 5. 
When to proceed to stage 3 assessments 
Patients should proceed to stage 3 assessments in the absence of biochemical disease. Patients 
with stimulated Tg < 1 ng/mL and TgAb negative (for the definition of TgAb negativity refer 
to Section 6.4.3.4) should proceed to stage 3 regardless of the WBS results. 
x
Note that if the stage 1 and 2 blood samples are discordant for TgAb, a repeat 
(third) blood sample for central analysis is required 10 days (±3 days) later. Only if 
the third sample is negative for TgAb will the stimulated Tg level from stage 2 be 
considered to be interpretable and valid for decision making. Refer also to Table 5. 
x
Note also that for study purposes the WBS will evaluated by blinded independent 
central review, and even if local interpretation of WBS scan data indicates uptake 
suspicious for DTC, any biochemically negative patients must still be sent for stage 
3 assessments (in case the local and central WBS results are discordant). 


Clinical Study Protocol 
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Edition Number 4 
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When not to proceed to stage 3 assessments 
All patients in the following situations will be classified not in complete remission and should 
not proceed to stage 3 assessments: 
1. 
Patients who have stimulated Tg level  1 ng/mL in the absence of TgAb 
(unequivocal biochemical disease by standardised central laboratory analysis). 
2. 
Patients confirmed to be TgAb positive (regardless of all other data): 
(a) 
When both the stage 1 and 2 blood samples are TgAb positive (refer to 
Section 6.4.3.4). 
(b) 
When the repeat (third) blood sample confirms positive TgAb following a 
discordant TgAb status from stage 1 and 2.  
In these situations the stimulated Tg value will be deemed to be uninterpretable, and the 
patient will be deemed not to be in complete remission because absence of biochemical 
disease cannot be proven.  
These patients will enter standard of care treatment/follow up at each centre as determined by 
the treating Investigator, and will continue to be followed in this study until 3 years following 
their initial RAI dose (refer to Section 6.4.6). 
Note that for study purposes the WBS will evaluated by blinded independent central review. If 
local interpretation of WBS scan data indicates uptake suspicious for DTC, any biochemically 
negative patients must still be sent for stage 3 assessments (in case the local and central WBS 
results are discordant).


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Edition Number 4 
Date 01 July 2014 
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Table 5 
Criteria for biochemical decision making (based on standardised central analysis results) 
Stage 1 
Stage 2 
Scenario 
Suppressed Tg 
TgAba 
Stimulated Tg 
TgAba 
Repeat 3rd TgAb 
sampleb 
Biochemical remission? 
1 
 1ng/mL 
Negative 
Not required 
Not required 
Not required 
No. Stop.c 
2 
< 1 ng/mL 
Negative 
< 1 ng/mL 
negative 
Not required 
Yes. Proceed to stage 3 
3 
< 1 ng/mL 
Negative 
 1 ng/mL 
negative 
Not required 
No. Stop.c 
4 
Any 
Positive 
< 1 ng/mL 
negative 
negative 
Yes. Proceed to stage 3 
5 
Any 
Positive 
< 1 ng/mL 
negative 
positive 
No. Stop.c 
6 
< 1 ng/mL 
Negative 
< 1 ng/mL 
positived 
negative 
Yes. Proceed to stage 3 
7 
< 1 ng/mL 
Negative 
< 1 ng/mL 
positive 
positive 
No. Stop.c 
8 
Any 
Positive 
Any 
positive 
Not required 
No. Stop.c 
a Standardised central methodology will be used to define TgAb negative/positive status, refer to Section 6.4.3.4. 
b When the TgAb results from stage 1 and 2 are discordant, a repeat (third) blood sample for TgAb is required 10 days (± 3 days) after the stage 2 blood 
sample. 
c For the purpose of the study, the patient will be deemed not to be in complete remission and no further stage 3 assessments are required. These patients will 
enter standard of care treatment/follow up at each centre as determined by the treating Investigator, and will continue to be followed in this study until 3 
years following their initial RAI dose (refer to Section 6.4.6). 
d Although this stimulated Tg blood sample is positive for TgAb, the patient will be declared to be in biochemical remission if the other two TgAb samples 
are both negative by standardised central analysis. It is not feasible to repeat a second stimulated Tg assessment.


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6.4.2.3 
Primary endpoint assessments Stage 3 
In stage 3, patients with biochemically-negative disease will have: 
x
Neck MRI with gadolinium contrast to be evaluated by blinded independent central 
review. 
x
Chest CT without contrast to be evaluated by blinded independent central review. 
x
If clinically indicated, a biopsy/FNA should be performed as follows: 

For any suspicious lymph nodes on MRI  15 mm in the smallest 
diameter ( 10 mm for level II, III or IV lymph nodes in the neck), or non 
nodal lesions  10 mm in the smallest diameter. 

For any chest abnormalities suspicious on CT  10 mm in the smallest 
diameter should be biopsied/FNA. 
6.4.3 
Blood sample assessments for efficacy 
All protocol-scheduled samples for serum Tg (suppressed and stimulated), TSH and TgAb 
assessment, will be sent for central laboratory analysis using standardised methodology. All 
decision making for study purposes will be based on the standardised central analysis results; 
values obtained from different assay methods may be different and cannot be used 
interchangeably.  
Full details of the sample collection, shipment and analytical methodology is provided in the 
Laboratory Manual. 
Unscheduled samples and local analysis: 
Investigators may also perform local biochemical analysis for these parameters as per standard 
site practice if desired, however this data will not be used for study-related decision making. If 
local analysis is performed, Investigators must ensure that the maximum permissible blood 
volumes for individual patients at their institutions are not exceeded.  
In the case that an investigator performs additional assessment of Tg (and TSH, TgAb) outside 
of the protocol scheduled visits, such samples should not be sent for central laboratory 
analysis. Only if such unscheduled local analysis leads the Investigator to wish to administer 
further therapy for thyroid cancer, should an additional sample ideally be sent for central 
analysis and the protocol-specified re-treatment criteria applied (Section 5.9.1.1) before the 
patient is re-treated.  
6.4.3.1 
Suppressed Tg 
Prior to the 18 month primary endpoint assessments: 
A blood sample for TSH-suppressed serum Tg is required at 9 months after the RAI dose 
(± 3 months) in order to assess whether thyroid cancer re-treatment is clinically indicated; 


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refer to the thyroid cancer re-treatment guidelines in Section 5.9.1.1. Tg assessment for this 
purpose may take place at any time from 6 months after the patient’s RAI treatment (but not 
before 6 months). A second blood sample 2-4 weeks later may also be required to verify the 
biochemical re-treatment criteria (refer to Section 5.9).  
Stage 1 primary endpoint assessments: 
For all patients that have not been re-treated for thyroid cancer prior to the primary endpoint 
assessments 18 months following their RAI dose, a blood sample to centrally analyse the 
TSH-suppressed serum Tg level will be taken. 
Anytime that a Tg blood sample is taken, the same sample will also be centrally analysed for 
TSH and TgAb (refer to Sections 6.4.3.3 and 6.4.3.4 respectively). 
The volume of blood for biochemical assessments is detailed in the Laboratory Manual for 
this study.  
6.4.3.2 
Stimulated Tg 
Prior to the 18 month primary endpoint assessments: 
Prior to the 18 month primary endpoint assessments, stimulated Tg levels are not 
recommended and not included as part of the patient follow up for this study.  
Stage 2 primary endpoint assessments: 
Serum Tg measured during TSH suppression is not sufficiently sensitive to confirm that a 
patient is free of thyroid cancer. For this reason, rhTSH (Thyrogen) stimulated serum Tg level 
will also be assessed at the primary endpoint, only for patients proceeding to stage 2 of the 
primary endpoint assessments. 
For patients that require stimulated Tg assessment, 0.9 mg of rhTSH will be administered IM 
for 2 consecutive days (refer to Section 5.5.4.1), with the blood sample taken for stimulated 
Tg central analysis on day 5. 
The volume of blood for biochemical assessments is detailed in the Laboratory Manual for 
this study.  
Each time that a blood sample is taken for central stimulated Tg analysis, the same sample 
will also be centrally analysed for TgAb (refer to Sections 6.4.3.4 respectively). 
6.4.3.3 
TSH 
Thyroid hormone supplementation will be adjusted in individual patients with the aim of 
achieving suppressed TSH levels of 0.5 mIU/L or less for the duration of the study.  Each time 
that a suppressed Tg sample is taken, TSH should also be assessed (by central standardised 
methodology). 


Clinical Study Protocol 
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The volume of blood for biochemical assessments is detailed in the Laboratory Manual for 
this study.  
6.4.3.4 
Tg antibody (TgAb)  
Each time that a blood sample is taken for central Tg analysis, the same sample will also be 
centrally analysed using standardised methodology for TgAb. Full details of the sample 
collection, shipment and analytical methodology to be used will be provided in the Laboratory 
Manual. 
TgAb cut-off for decision making 
For decision making purposes at any time in the study, standardised central analysis results 
must be used. The cut-off value for positive/negative TgAb status according to the 
standardised central methodology will be provided to sites prior to the start of recruitment. 
At screening: 
Patients with TgAbs present at screening will be ineligible for the study (refer to the exclusion 
criterion in Section 4.2, screening samples must be sent for standardised central analysis). 
Prior to the 18 month primary endpoint assessments: 
If TgAbs are detected in the follow-up Tg blood sample (at 9 months ±3 months), the patient 
should not be re-treated unless new structural disease is detected according to Section 5.9.1.2 
(ie, it is strongly recommended that patients are not re-treated on the basis of new antibodies 
alone, in the absence of structural disease). Refer to Section 5.9. 
Primary endpoint assessments (Stage 1 and 2) 
The TgAb status of the stage 1 blood sample will not be taken into consideration alone. The 
following rules will apply (refer also to Table 5): 
1. 
If both stage 1 and stage 2 blood samples are negative for TgAb, then the Tg results 
will be valid for decision making. 
2. 
If both stage 1 and stage 2 blood samples are positive for TgAb, then the stimulated 
Tg result will be deemed to be uninterpretable, and for the purpose of this study the 
patient will be classified as not in complete remission. No further primary endpoint 
assessments are required.  
3. 
If the stage 1 and 2 blood samples are discordant for TgAb status, then a repeat 
(third) blood sample is required 10 days later (± 3 days). Only if the repeat sample 
is confirmed negative for TgAb, will the stimulated Tg level in stage 2 be 
considered to be interpretable and valid for decision making.   


Clinical Study Protocol 
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Edition Number 4 
Date 01 July 2014 
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6.4.4 
Imaging assessments for efficacy 
6.4.4.1 
Neck ultrasound (US) 
Neck US assessments will take place at the times indicated in the Study Plan Table 3.  Refer 
also to Section 6.4.2 and Table 4 for further details of US assessment at the primary endpoint. 
Any suspicious lymph nodes or lesions in the neck  5 mm in the smallest diameter identified 
by US during the study should be biopsied/FNA. 
Note: for a lesion to be suspicious it must be new or enlarged compared to the previously 
obtained imaging data, and be consistent with the biological characteristics of DTC. 
Biopsy/FNA samples, where performed, will be assessed at each site. Needle washout may be 
analysed locally for Tg according to local standard practice. The totality of the information 
obtained from a biopsy/FNA (including washout Tg data where analysed), will be assessed 
locally to determine presence or absence of thyroid cancer in the sample. 
US definition of structural DTC 
Any soft tissue or lymph node lesions that are new or enlarged compared to previous 
ultrasound assessment (either post operatively and/or at 9 months) that are consistent with the 
biological characteristics of DTC and fulfil the following criteria will be considered as 
structural thyroid cancer: 
x
Lesions of any size confirmed to be structural DTC by positive biopsy/FNA (ie, 
biopsy proven). 
x
Any suspicious lesion or lymph node of any size that is subsequently shown to be 
RAI avid/positive on central review of WBS (in this situation the positive WBS 
data takes precedent over a negative biopsy/FNA from the same lesion/lymph node 
if performed).  
Note, any abnormality on US that is non-RAI avid on the subsequent WBS, will be considered 
benign even in the absence of a biopsy. 
The assessment of neck US and biopsy/FNA sample will be made by investigator site review. 
The local ultrasound information will be recorded in the eCRF (with FNA/biopsy results if 
performed) and provided to the central imaging CRO if necessary as supporting clinical data 
(refer to Section 6.4.4.6).     
Guidelines for standardised acquisition, defining suspicious lesions and reporting of US 
assessments required for this study will be provided to each study site. 


Clinical Study Protocol 
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6.4.4.2 
Whole body diagnostic 131I nuclear medicine scan (WBS) 
Pre-RAI treatment 
There is no pre-ablation WBS in this study. This is a fixed RAI dose study (100mCi, 3.7GBq) 
with Thyrogen stimulation. Study-specific post-operative imaging will be used to ensure that 
enrolled patients do not have overt macronodular disease remaining in the neck or distant 
metastatic disease in the lungs.  
Post-RAI treatment 
All randomised patients will have a WBS performed 3-10 days following their RAI treatment 
dose to assess where the administered 131I has localised. 
It is acknowledged that this assessment may identify a small number of patients with distant 
metastatic disease that was not previously identified (patients with known metastatic disease 
at study entry will be excluded). Such patients will continue in the study and should not be 
withdrawn; they will continue to be followed according to the protocol and will be included in 
both the Intention To Treat (ITT) efficacy and safety analysis sets for the study. 
Primary endpoint (stage 2) 
If required according to Section 6.4.2, the diagnostic WBS to assess the primary endpoint will 
be performed following a diagnostic dose of 5 mCi 131I (refer to Section 5.5.4.2). Patients will 
receive 2 Thyrogen injections on consecutive days (day 1 and 2), followed by a diagnostic 
dose (5 mCi) of 131I on either day 2 or day 3, and a blood draw for stimulated Tg central 
assessment and WBS both on day 5. Patients will be required to adhere to a low iodine diet for 
a period of 1 week before the diagnostic 131I dose, until the diagnostic WBS assessment is 
completed. 
Standardised acquisition and submission guidelines for every WBS procedure will be 
provided separately to this protocol. 
WBS definition of structural DTC 
The WBS evaluation will be made by blinded, independent central review. 
If the central review determines no visible 131I uptake then the WBS for that patient will be 
considered normal/negative (no disease).  Areas considered to be anatomically normal (for 
example uptake in the salivary glands, stomach, gastrointestinal, urinary tract and bladder) 
will not be considered disease. 
If the central review determines there is a low level of visible uptake in the thyroid bed: 
x
Uptake must be < 0.1% to be considered normal/negative (no disease). 
x
If uptake in the thyroid bed region is  0.1%, the patient will be deemed not to be in 
remission due to the presence of iodine-avid DTC. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
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Edition Number 4 
Date 01 July 2014 
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The % uptake in the thyroid bed will be assessed by the Investigator site according to the local 
clinical practice and entered into the eCRF to be made available to the central reviewer. 
If an abnormality identified by US is subsequently shown to be RAI avid on WBS, the WBS 
data takes precedent over a negative biopsy/FNA. 
6.4.4.3 
Neck MRI 
Post-operative (screening) 
This baseline assessment is performed to determine study eligibility according to Section 4.1).  
The baseline post-operative images will be available at the central imaging CRO to aid 
interpretation of the primary endpoint image central read if necessary (refer to Section 6.3). 
Primary endpoint (stage 3) 
Neck MRI to define the primary endpoint will be performed in stage 3 of the assessments in 
patients deemed to be biochemically-negative for thyroid cancer. Refer to Section 6.4.2.3 and 
Figure 3. 
The neck MRI must be performed using T1 weighted image sequences with and without 
gadolinium contrast agent, and T2 weighted image sequences. 
If clinically indicated, any suspicious lymph nodes on MRI  15 mm in the smallest diameter 
( 10 mm for level II, III or IV lymph nodes in the neck), or non nodal lesions  10 mm in the 
smallest diameter, should be biopsied/aspirated by fine needle.  
MRI definition of structural DTC 
New lesions (nodal or non-nodal) or significantly enlarged lymph node lesions compared to 
previous post operative (screening) MRI which are consistent with the biological 
characteristics of DTC and fulfil either of the following criteria will be considered to represent 
structural thyroid cancer: 
x
Lesions of any size confirmed to be structural DTC by positive biopsy/FNA (ie, 
biopsy proven). 
x
Any suspicious lesion or lymph node of any size that is shown to be RAI 
avid/positive on WBS (in this situation the positive WBS data takes precedent over 
a negative biopsy/FNA from the same lesion/lymph node if performed).  
Note, any abnormality on MRI that is non-RAI avid on the WBS, will be considered benign 
even in the absence of a biopsy. 
This assessment will be made by blinded, independent central review. 


Clinical Study Protocol 
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Study Code D1532C00065 
Edition Number 4 
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6.4.4.4 
Chest CT 
In this study all chest CT procedures should be performed without iodine containing contrast 
agent. 
Post-operative (screening) 
This baseline assessment is performed to determine study eligibility according to Section 4.1).  
The baseline post-operative images will be available at the central imaging CRO to aid 
interpretation of the primary endpoint image central read if necessary (refer to Section 6.3). 
Primary endpoint (stage 3) 
Chest CT to define the primary endpoint will be performed in stage 3 of the assessments in 
patients deemed to be biochemically-negative for thyroid cancer. Refer to Section 6.4.2.3 and 
Figure 3. 
If clinically indicated, any chest abnormalities suspicious on CT  10 mm in the smallest 
diameter should be biopsied/FNA. 
CT definition of structural DTC 
New lesions (nodal or non-nodal) or significantly enlarged lymph node lesions compared to 
previous post operative (screening) CT which are consistent with the biological characteristics 
of DTC and fulfil either of the following criteria will be considered to represent structural 
thyroid cancer: 
x
Lesions of any size confirmed to be structural DTC by positive biopsy/FNA (ie, 
biopsy proven). 
x
Any suspicious lesion or lymph node of any size that is shown to be RAI 
avid/positive on WBS (in this situation the positive WBS data takes precedent over 
a negative biopsy/FNA from the same lesion/lymph node if performed).  
Note, any abnormality on CT that is non-RAI avid on the WBS, will be considered benign 
even in the absence of a biopsy. 
This assessment will be made by blinded, independent central review  
6.4.4.5 
Biopsy or fine needle aspirate (FNA) 
A biopsy or FNA should be performed in the following situations: 
x
US: For any suspicious lymph nodes or lesions in the neck  5 mm in the smallest 
diameter identified by US during the study. 
x
MRI: If clinically indicated, for lymph nodes suspicious on MRI  15 mm in the 
smallest diameter ( 10 mm for level II, III or IV lymph nodes in the neck), or non 
nodal lesions  10 mm in the smallest diameter. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
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x
CT: If clinically indicated, for any chest abnormalities suspicious on CT  10 mm 
in the smallest diameter. 
Note: for a lesion to be suspicious it must be new or enlarged compared to the previously 
obtained imaging data, and be consistent with the biological characteristics of DTC. 
All biopsy/FNA samples taken during the study will be assessed at each site according to local 
standard practice. Needle washout may be analysed locally for Tg according to local standard 
practice (this is not a mandatory requirement). The totality of the information obtained from a 
biopsy/FNA (including washout Tg data where analysed), will be assessed locally to 
determine presence or absence of thyroid cancer in the sample. This information will be 
provided to the central imaging CRO. 
Refer to Section 6.10.3 for details regarding tumour sample acquisition on disease 
progression. 
6.4.4.6 
Information to be sent to the central imaging CRO 
The following information will be sent to the central imaging CRO (further details are 
provided in the imaging charter/guidelines for this study). 
1. 
Post-operative screening assessments (refer to Section 6.3): images for chest CT 
and neck MRI. This data must be sent for all patients as soon as possible after each 
patient is randomised.  
2. 
Post-RAI WBS images taken 3-10 days after each patient’s RAI dose. This data 
must be sent for all patients as soon as possible after each patient has their post-RAI 
WBS assessment. 
3. 
Primary endpoints assessments stage 1: site ultrasound and biopsy information. The 
required data must be entered into the clinical database for each patient as soon as 
possible after completion of the assessment (NOTE: this information is not sent to 
the central imaging CRO, but instead must be entered into the database directly 
using eCRF). 
4. 
Primary endpoint assessments stage 2: diagnostic WBS images. This data must be 
sent for all patients as soon as possible after completion of the assessment. 
5. 
Primary endpoint assessments stage 3: chest CT and neck MRI images and biopsy 
information (if performed). This data must be sent for all patients as soon as 
possible after completion of the assessments. Biopsy data must be entered into the 
clinical database for each patient as soon as possible after completion of the 
assessment. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
84(120) 
6.4.5 
Derivation of primary endpoint of complete remission 
The complete remission status of each patient will be determined programmatically by 
AstraZeneca, by incorporating data on re-treatment provided by the site, biochemical data 
from the standardised central laboratory analysis, and structural disease assessment from the 
blinded, independent central review.  
If a patient has received further therapy for thyroid cancer prior to the primary endpoint 
assessment, the patient will be classified as not in complete remission and no further data will 
be considered. 
For patients that have not received further therapy for thyroid cancer, all available imaging 
data will be sent to the imaging CRO.  Determination of presence or absence of structural 
thyroid cancer will be made by the imaging CRO only for biochemically negative patients. A 
list of biochemically negative patients (based on standardised central laboratory analysis) will 
be provided by AstraZeneca to the imaging CRO to enable them to identify which patients to 
assess. 
The imaging CRO will assess the WBS, MRI and CT and also review the site assessment of 
neck US to provide an overall assessment: presence or absence of structural thyroid cancer, or 
not evaluable based on all of the available information. For the derivation of the complete 
remission endpoint, patients that are not evaluable for structural disease assessment will be 
considered as not achieving complete remission, regardless of the result of other assessments.    
AstraZeneca will programmatically combine information on further therapy, biochemical data, 
and the determination of structural disease from the central imaging CRO, to determine the 
complete remission status of each patient as shown in Table 6. 
The dates on which assessments were performed will be incorporated into the derivation of 
the primary endpoint to ensure patients are assessed within a time window around the 
scheduled 18 month post-RAI treatment. The first assessment must be started at 18 months 
± 2 weeks following the patient’s RAI dose, and all necessary primary endpoint assessments 
must be completed within a 8 week period. If a patient has assessments/scans that fall outside 
of these time windows, the patient will be considered not to be in complete remission, 
regardless of the assessment of disease status. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
85(120) 
Table 6 
Programmatic derivation of complete remission status 
Biochemical datab 
Scenario 
Further 
thyroid cancer 
therapya       
(re-treatment) 
Stimulated Tgb 
TgAbb 
Structural 
disease 
assessmentc 
Complete 
remission 
1 
Yes 
N/A 
N/A 
N/A 
No 
2 
No 
< 1 ng/mL 
Negatived 
Absence of 
disease 
Yes 
3 
No 
 1ng/mL 
Any 
Any 
No 
4 
No 
Any 
Positived 
Any 
No 
5 
No 
Any 
Any 
Presence of 
disease 
No 
6 
No 
NE 
Any 
Any 
No 
7 
No 
Any 
NE 
Any 
No 
8 
No 
Any 
Any 
NE 
No 
a As assessed by investigator at site. 
b As assessed by standardised central laboratory analysis. 
c As assessed by blinded, independent central review. 
d  If the stage 1 and 2 blood samples are discordant for TgAb status, then a third blood sample 10 days later (± 3 days) is required. Only if the third sample is 
negative for TgAb will the overall TgAb result be considered negative for the primary endpoint assessments. Refer also to Table 5. 
N/A primary endpoint assessments are not required for patients that have received further treatment for thyroid cancer in the previous 18 months. 
NE Not evaluable (for example due to missing samples or assessments). 
 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
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6.4.6 
Clinical remission 
The secondary efficacy endpoint for this study is clinical remission rate at 18 months 
(following RAI treatment). This is designed to more typically reflect clinical practice. As 
such, the definition of clinical remission will exclude the additional radiological assessments 
performed for the purpose of complete remission in this study. 
Definition of clinical remission: 
Patients will be defined to be in clinical remission if all of the following criteria can be 
demonstrated: 
1. 
Serum Tg levels < 1ng/mL during rhTSH stimulation, in the absence of interfering 
Tg antibodies, as assessed by standardised central laboratory analysis. 
2. 
No confirmed evidence of thyroid cancer on neck US, as assessed by investigator 
site review. 
3. 
No evidence of thyroid cancer on diagnostic WBS, as assessed by blinded 
independent central review.  
4. 
No histopathological evidence of thyroid cancer on FNA/biopsy when performed to 
clarify equivocal US findings, as assessed by investigator site review. 
5. 
No further thyroid cancer therapy was administered in the first 18 months following 
the initial RAI treatment.  
6.4.7 
Derivation of clinical remission status 
The clinical remission status of each patient will be determined programmatically by 
AstraZeneca, by incorporating data on re-treatment provided by the site, biochemical data 
from the standardised central laboratory analysis, structural disease assessment based on US 
by investigator site review and structural disease assessment based on WBS from the blinded, 
independent central review.  
If a patient has received further therapy for thyroid cancer prior to the primary endpoint 
assessment, the patient will be classified as not in clinical remission and no further data will 
be considered. 
For patients that have not received further therapy for thyroid cancer: 
A determination of presence or absence of structural thyroid cancer or not evaluable will be 
made by the investigator based on US.  
A determination of presence or absence of structural thyroid cancer or not evaluable will be 
made by the central imaging CRO based on WBS for only biochemically negative patients. 
Information on US will not be reviewed as part of this assessment. A list of biochemically 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
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Edition Number 4 
Date 01 July 2014 
87(120) 
negative patients (based on standardised central laboratory analysis) will be provided by 
AstraZeneca to the imaging CRO to enable them to identify which patients to assess. 
AstraZeneca will programmatically combine information on further therapy, biochemical data, 
determination of structural disease from the investigator site assessment of US and 
determination of structural disease from the central imaging CRO of WBS, to determine the 
clinical remission status of each patient.  
Full details of the programmatic derivation of clinical remission will be provided in the SAP. 
6.4.8 
Final study follow up at 3 years 
The final study follow-up will take place 3 years post-RAI for each patient, and will include: 
1. 
The clinical status of each patient, for example: remission, persistent disease, 
recurrent disease, survival status. 
2. 
The incidence of further therapy (re-treatment) for thyroid cancer, for example, 
additional RAI or surgery. 
3. 
Final assessment of selumetinib or RAI-related AEs and SAEs. 
Note, following the primary endpoint assessments until the final study visit at 3 years 
following each patient’s initial RAI treatment, each patient will enter standard of care 
treatment or follow up according to local practice. No study-specific assessments will be 
performed, and locally performed assessments and data will not typically be collected as 
routine in the clinical study database (except for safety data, refer to Section 6.5.3). The 
patient’s clinical status at the final study follow up will be collected (along with any relevant 
supporting local assessment data). For example, remission status will be defined by the 
Investigator on the eCRF based on the relevant local standard of care assessments (eg, locally 
assessed Tg and no evidence of thyroid cancer on locally assessed US). 
6.5 
Safety 
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. 
6.5.1 
Definition of adverse events  
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition 
can be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the 
abnormal results of an investigation (eg, laboratory findings, electrocardiogram).  In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered. 
The term AE is used to include both serious and non-serious AEs. 


Clinical Study Protocol 
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6.5.2 
Definitions of serious adverse event 
A serious adverse event is an AE occurring during any study phase (ie, run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria: 
x
Results in death 
x
Is immediately life-threatening 
x
Requires in-patient hospitalisation or prolongation of existing hospitalisation  
x
Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions 
x
Is a congenital abnormality or birth defect 
x
Is an important medical event that may jeopardise the patient or may require 
medical intervention to prevent one of the outcomes listed above 
For further guidance on the definition of a SAE, see Appendix B to the Clinical Study 
Protocol. 
6.5.3 
Recording of adverse events 
All adverse events will be graded according to NCI CTCAE Version 4. 
Time period for collection of adverse events 
All AEs/SAEs will be collected from informed consent until 30 days following the last dose of 
study treatment (selumetinib or placebo).  
After this time: 

all SAEs regardless of causality will be collected until the final study 
follow-up (3 years post-RAI for each patient, refer to Section 6.4.8) 

only AEs considered causal to RAI or the combination of RAI and study 
treatment will be collected until the final study follow-up (3 years post-
RAI for each patient, refer to Section 6.4.8). 
Follow-up of unresolved adverse events 
Any AE or laboratory change occurring during the study treatment period should be followed 
up by the investigator for as long as medically indicated (resolution or stabilisation), and 
follow up information  recorded in the eCRF. 
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the CRF. 


Clinical Study Protocol 
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Date 01 July 2014 
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AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
Variables 
The following variables will be collected for each AE: 
x
AE (verbatim) 
x
The date when the AE started and stopped 
x
CTCAE grade information 
x
Whether the AE is serious or not 
x
Investigator causality rating against the Investigational Product (yes or no) and/or 
RAI (yes or no) 
x
Action taken with regard to investigational product 
x
AE caused patient’s withdrawal from study treatment 
x
Treatments patient received for AE 
x
Outcome 
x
Whether event constitutes an SAE. 
In addition, the following variables will be collected for SAEs: 
x
Date AE met criteria for serious AE 
x
Date Investigator became aware of serious AE 
x
AE is serious due to 
x
Date of hospitalisation 
x
Date of discharge 
x
Probable cause of death (if applicable) 
x
Date of death (if applicable) 
x
Autopsy performed (if applicable) 
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.5.2.  An AE of severe 


Clinical Study Protocol 
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Date 01 July 2014 
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intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE. On the other hand, a stroke 
that results in only a limited degree of disability may be considered a mild stroke but would be 
a SAE. 
Causality collection 
The Investigator will assess causal relationship between Investigational Product and RAI and 
each Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’ 
For SAEs causal relationship will also be assessed for other medication, study procedures and 
additional study drug (eg, RAI).  Note that for SAEs that could be associated with any study 
procedure the causal relationship is implied as ‘yes.’ 
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol. 
Adverse Events based on signs and symptoms 
All AEs spontaneously reported by the patient, or reported in response to the open question 
from the study personnel: ‘Have you had any health problems since the previous visit/you 
were last asked?’ or revealed by observation, will be collected and recorded in the CRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately. 
Adverse Events based on examinations and tests 
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
clinical study report.  Deterioration as compared to baseline in protocol-mandated laboratory 
values, vital signs etc should therefore only be reported as AEs if they fulfil any of the SAE 
criteria or are the reason for discontinuation of treatment with the investigational product. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s). 
After the 30 day follow up visit, AEs associated with RAI or the combination of study 
treatment and RAI, should continue to be collected by AE reporting, these would include 
abnormalities, for example, white blood cell count or Hb reductions.  
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
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Edition Number 4 
Date 01 July 2014 
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Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
Cases where a patient shows an AST or ALT 3xULN or total bilirubin  2xULN may need 
to be reported as SAEs, please refer to Appendix D ‘Actions required in cases of combined 
increase of aminotransferase and total bilirubin – Hy’s Law,’ for further instructions. All 
patients with an AST, ALT or bilirubin value above ULN at time of the last dose of 
selumetinib/placebo should have a further liver chemistry profile (AST, ALT, bilirubin and 
ALP) performed 30 days (± 7 days) later for follow-up. 
6.5.3.1 
Disease progression 
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the investigational product is being studied.  It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease.  Events, 
which are unequivocally due to disease progression, should not be reported as an AE during 
the study. 
6.5.4 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the CRF. 
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
appropriate AstraZeneca representatives immediately, or no later than 24 hours of when he 
or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within one 
calendar day of initial receipt for fatal and life threatening events and within five calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative. 
If the WBDC system is not available, then the Investigator or other study site personnel 
reports a SAE to the appropriate AstraZeneca representative by telephone. 
The AstraZeneca representative will advise the Investigator/study site personnel how to 
proceed. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
92(120) 
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug. 
6.5.5 
Laboratory safety assessment 
Blood and urine samples for determination of clinical chemistry, haematology and urinalysis 
will be taken at the times indicated in the Study Plan (Table 3). For samples taken after Day 1 
during the study treatment period, the sample may be taken any time of day (ie, it does not 
matter whether it is pre-dose or post-dose). Day 1 samples should be taken pre-dose. 
The following laboratory variables will be measured: 
Table 7 
Laboratory safety assessments 
Clinical chemistry 
Haematology 
Urinalysis a 
s, p-Albumin 
Erythrocyte count 
u-Albumin 
s, p-ALT 
Haemoglobin 
u-Creatinine 
s, p-AST 
Platelet count 
 
s, p-ALP 
Leucocyte cell count 
 
s, p-Total Calcium 
Leucocyte differential count   
(absolute count or percentage): 
 
s, p-Creatinine 
Neutrophils 
 
s, p-Gamma glutamyl transferase (JGT) 
Eosinophils 
 
s, p-Glucose 
Basophils 
 
s, p-Magnesium 
Lymphocytes 
 
s, p-Phosphate 
Monocytes 
 
s, p-Potassium 
 
 
s, p-Sodium 
 
 
s, p-Total protein 
 
 
s, p-Total bilirubin 
 
 
s, p-Urea nitrogen 
 
 
s, p-Creatine kinase 
 
 
a A single-spot urine specimen will be collected on the day of scheduled visit, at sites where the local laboratory 
is able to determine the concentration of urine albumin and urine creatinine from a single-spot urine specimen.  
Investigational sites unable to report these parameters will perform routine urinalysis according to the local 
standard of care.  
s, p serum, plasma 
u urine  
 
All laboratory safety assessments will be analysed by the local laboratory. 
Clinical chemistry, haematology and urinalysis testing will be repeated as clinically indicated 
as part of the routine management of the patient on the occurrence of AEs. 
For blood volume see Table 9. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
93(120) 
6.5.6 
Physical examination 
A complete physical examination will be performed at the times indicated in the Study Plan 
Table 3. 
6.5.7 
Cardiac monitoring 
Note: troponin assessment in this study is only required for cardiac AE follow up as clinically 
indicated. 
6.5.7.1 
ECHO or MUGA 
An ECHO or MUGA assessment (according to site preference) will be conducted at the 
timepoints indicated in the Study Plan (Table 3). A further assessment should be performed as 
part of the assessment package for any cardiorespiratory adverse event with no obvious 
diagnosis.  Medical management of the event should follow local clinical practice.  
Selumetinib interruption should be considered until resolution of the event or until return to 
baseline. 
LVEF can be measured in many different ways but echography is the preferred choice when 
possible.  The same modality should be used as baseline for any ECHO/MUGA follow up. 
Recommendations include  having complete high quality standardized 2-D with Doppler 
echocardiographic examinations performed by an experienced sonographer (preferably with 
the same operator performing all studies for a given patient), according to a specified protocol 
including evaluation of both systolic and diastolic left ventricular function.  Ejection fraction 
determinations should be assessed quantitatively based on bi-plane measurements of end 
diastolic and end systolic left ventricular volumes. 
6.5.7.2 
Resting 12-lead ECG 
ECGs will be analysed locally at each site.  Patients should be supine and at rest 10 minutes 
prior to recording the ECG. 
Parameters including heart rate, duration of QRS complex, PR and QT intervals will be 
collected.  R-R interval and QTcF will be calculated by AstraZeneca from the data provided. 
The investigator should review the paper copy of the ECGs on each study day and may refer 
to a local cardiologist if appropriate. 
Any symptoms from the patient should be registered as a comment and if AE criteria are met, 
recorded as an AE. 
At screening all patients will have a single 12-lead ECG performed.  The screening ECG can 
be conducted up to 28 days prior to randomisation. 
During the treatment phase of the study, patients will have single 12-lead ECGs assessments 
at the following timepoints: 
x
1-2 hours after the first dose of study treatment on Day 1 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
94(120) 
x
1-2 hours after the morning dose of study treatment on Day 29 or 30 
x
At the 30-day follow up visit following completion of study treatment   
x
Single ECGs must also be performed at the time of any ECHO/MUGA assessment, 
and on occurrence of any cardiorespiratory adverse event   
x
A single 12-lead ECG is also required at premature discontinuation of treatment 
6.5.8 
Vital signs 
Resting blood pressure and pulse rate will be measured using a semi-automatic blood pressure 
recording device with an appropriate cuff size.  Vital sign assessments, including weight, will 
be performed at the times indicated in the Study Plan Table 3. Pulse and blood pressure must 
also be performed at the time of any ECHO/MUGA assessment, and on occurrence of any 
cardiorespiratory adverse event.  Height will be assessed at Visit 1 only.   
Any changes in vital signs should be recorded as an AE if applicable. 
6.5.9 
Other safety assessments 
6.5.9.1 
Pregnancy test 
A serum or urine pregnancy test (according to local practice) will be performed at the times 
indicated in the Study Plan Table 3. Following the RAI treatment, monitoring for pregnancy 
will be performed according to standard clinical practice at each centre. 
6.5.9.2 
Ophthalmologic examination 
An ophthalmologic examination (best corrected visual acuity, intraocular pressure, slit lamp 
fundoscopy) should be performed at the timepoints indicated in the Study Plan (Table 3), and 
if a patient experiences a visual symptoms (including blurring of vision) with additional tests 
if clinically indicated e.g. consider OCT scans. 
Patients who have a retinal abnormality prior to discontinuation of selumetinib/placebo should 
have a follow up eye examination performed within 30 days after discontinuation of 
selumetinib/placebo in order to document reversibility. 
An algorithm for management and investigation of visual symptoms is provided in 
Appendix G: “Guidance for Management of Adverse Events in Studies of Selumetinib.” 
6.6 
Patient reported outcomes (PRO) – not applicable 
Patient reported outcomes will not be collected in this study. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
95(120) 
6.7 
Pharmacokinetics  
6.7.1 
PK samples required 
Blood samples (2 mL) for determination of plasma concentrations of selumetinib and 
N-desmethyl selumetinib will be collected from every patient according to the time points 
below.  Other metabolites (eg, selumetinib amide) may also be determined in the PK analysis. 
Each patient will be asked to contribute 8 blood samples, one from each of the pre defined 
time windows below on both Day 1 and Day 29 or Day 30.  The Day 29 or Day 30 PK blood 
samples may be taken earlier, from Day 22 onwards of study treatment if preferred, but it is 
essential that all PK blood samples are collected on a visit day prior to the RAI dose being 
administered.  
x
Pre-dose (within 15 minutes of dosing) 
x
Between 15 minutes and 1 hour post-dose 
x
Between 1.5 and 2.5 hours post-dose 
x
Between 3 and 8 hours post-dose 
Depending on emerging data/information, the timings and number of the PK samples may be 
altered, but the maximum total blood volumes given in Table 9 will not be exceeded.  The 
actual sample date and time of all PK samples must be recorded in the eCRF. 
Samples will be collected, labelled, stored and shipped as detailed in Laboratory Manual.  
6.7.2 
Determination of drug concentration 
Samples for determination of selumetinib and N-desmethyl selumetinib concentrations in 
plasma will be analysed by Covance on behalf of Clinical Bioanalysis Alliance, AstraZeneca 
R&D, using an appropriate bioanalytical method. Other metabolites (eg, selumetinib amide) 
may also be determined in the PK analysis. Full details of the bioanalytical method used will 
be described in a separate bioanalytical report. 
For each placebo patient, samples will only be analysed on a ‘for cause’ basis, for example, if 
no quantifiable concentrations were observed in a patient’s samples when the drug was 
expected to be present. 
All samples still within the known stability of the analytes of interest (ie, selumetinib, N-
desmethyl selumetinib and its metabolites) at the time of receipt by the bioanalytical 
laboratory will be analysed. 
6.8 
Pharmacodynamics – not applicable 
Pharmacodynamic samples will not be taken during this study.  


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
96(120) 
6.9 
Pharmacogenetics 
6.9.1 
Genetic blood sample at study entry 
An optional blood sample for genetic research will be obtained from eligible patients at Visit 1 
or 2 ideally.  If for any reason the sample is not drawn at Visit 1 or 2, it may be taken at any 
visit before the RAI dose is administered (radioactive samples for this purpose will not be 
accepted).  Although genotype is a stable parameter, early sample collection is preferred to 
avoid introducing bias through excluding patients who may withdraw due to an adverse event 
(AE), such patients would be important to include in any genetic analysis.  Only one sample 
should be collected per patient for this purpose.  Samples will be collected, labelled, stored 
and shipped as detailed in the Laboratory Manual. 
For blood volumes see Section 7.1. 
6.10 
Biomarker analysis 
6.10.1 
BRAF and NRAS patient population 
Archival tumour sample from each patient will be analysed for BRAF and NRAS mutational 
status centrally using standardised methodology. Analysis may include, but is not limited to, 
BRAF V600E and NRAS Q61R, Q61K, Q61L.Full analytical methodology details will be 
provided in the CSR. 
The genetic analysis of archival tumour samples to identify the BRAF and NRAS patient 
population will be performed retrospectively in the study (after randomisation but prior to the 
primary endpoint data analysis). 
BRAF/NRAS positive = mutations in BRAF/NRAS have been detected 
BRAF/NRAS not detected = no mutation in BRAF/NRAS has been detected   
BRAF/NRAS unknown = mutation status in BRAF/NRAS cannot be confirmed 
6.10.1.1 Archival tumour sample 
All patients will be required to provide consent for AstraZeneca to collect and analyse 
samples of their previously obtained tumour material (ie, from their recent surgery) for 
analysis of biomarkers relevant to DTC. Archival tumour sample provision is mandatory in 
this study, and each Investigator should make every effort to collect a sample from all 
randomised patients.  It is accepted that it may not be possible to obtain all samples prior to 
commencement of study treatment (which should continue as planned).  However, it should be 
established during the screening period that sufficient sample exists and is available. Samples 
are expected to be made available as soon as possible. Note, no replacements will be made for 
patients where an archival tumour sample is not provided. 
These samples will be analysed for the biomarkers necessary for the definition of the second 
primary objective patient population (BRAF and NRAS mutational status), and may also be 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
97(120) 
used for exploratory analyses on residual material. Such analyses may include (but are not 
restricted to): 
x
Mutational status of BRAF and NRAS genes, RET rearrangements, and other known 
MAPK and PI3K effector oncogenes.  
x
Baseline expression of pathway and thyroid differentiation specific genes such as 
NIS, Tg, TPO, and PAX8. 
x
Comprehensive genetic analysis to ensure coverage of the major mutational events 
in DTC. 
The exploratory analyses from tumour material may include but are not limited to mRNA 
expression profiling, microRNA expression profiling, gene copy number analysis and protein 
expression by immunohistochemistry for any markers relevant to DTC, either known at the 
time of analysis, or identified in the future. 
For the tumour samples detailed below, each site will be asked to provide one of the following 
for each randomised patient: 

Formalin-fixed, paraffin-embedded tumour tissue block, 
or 

20 pre-cut sections from formalin-fixed paraffin-embedded tumour tissue 
block, presented on slides. Each section is to be 5 ȝm thick.  
Sites should ship the tumour sample as soon as it is available.  If mutational status cannot be 
adequately determined from the initial tumour biopsy sample, and histopathological review 
shows it to be a poor quality sample, a second sample should be submitted for re-testing.   
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual. 
If requested, unused tumour samples will be repatriated.  For further details see the Laboratory 
Manual. 
6.10.2 
Collection of plasma and serum for exploratory biomarker research 
All randomised patients will be required to provide a blood sample at or before randomisation, 
and disease progression (for example, when the patient is re-treated for persistent or recurrent 
thyroid cancer) for exploratory biomarker research. 
All patients will be required to provide: 

1x 10ml blood sample for preparation of serum at randomisation (any 
time before the first dose of study treatment for eligible patients) and 
disease progression. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
98(120) 

1x 10ml blood sample for preparation of plasma at randomisation (any 
time before the first dose of study treatment for eligible patients) and 
disease progression. 
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual. 
Residual material may be used for exploratory biomarker research. 
6.10.3 
Collection of disease progression tumour sample 
Patients will be asked to provide a tumour sample removed during the study when the patient's 
cancer is deemed to have progressed (for example, when the patient is re-treated for persistent 
or recurrent thyroid cancer, or has had further surgery). This is an optional sample. 
This will enable a comparison to be made of (for example) tumour genetics and relevant 
signal transduction pathways between the randomisation and the disease progression tumour 
sample and also the evolution of the tumour biology in response to treatment with selumetinib 
can be explored. Such changes may reflect an evolution in phenotype of the tumour, which 
ultimately may guide future treatment decisions post progression on selumetinib. 
Samples can be of any type (such as FNA, or tumour sample taken from a surgical procedure 
performed as part of the patient’s disease management plan), and will be collected, labelled, 
stored and shipped as detailed in the Laboratory Manual. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
99(120) 
Table 8 
Biomarker summary table 
Biomarker sample 
Time point 
Protocol Section 
Archival tumour for NRAS and BRAF 
analysisa 
Randomisation 
6.10.1.1 
Plasma sample for exploratory biomarker 
analysis 
Randomisation and disease 
progression 
6.10.2 
Serum sample for exploratory biomarker 
analysis 
Randomisation and disease 
progression 
6.10.2 
Disease progression tumour biopsy 
(optional) 
Disease progression 
6.10.3 
Blood sample for genetic analysis 
(optional) 
Randomisation 
6.9.1 
a Residual tissue sample material will be stored for potential retrospective biomarker analysis, which will be 
performed in an AstraZeneca laboratory or AstraZeneca approved laboratory. 
7. 
BIOLOGICAL SAMPLING PROCEDURES  
7.1 
Volume of blood 
The total volume of blood (maximum) that will be drawn from each patient in this study is as 
follows: 
Table 9 
Volume of blood to be drawn from each patient  
Assessment 
Maximum 
sample 
volume a 
(mL) 
Typical 
number of 
samples (over 
18+ months) 
Total volume 
(mL) 
Safety 
Clinical chemistry (local analysis) 
5 
5 
25 
 
Haematology (local analysis) 
3 
7 
21 
Efficacy 
Tg, TSH, TgAb (central analysis) 
10 
4b 
40 
PK 
2 
8 
16 
Genetics at randomisation (optional) 
10 
1 
10 
Exploratory biomarkers at randomisation, serum  
10 
1 
10 
Exploratory biomarkers at randomisation, plasma  
10 
1 
10 
Exploratory biomarkers on progression, serum  
10 
1 
10 
Exploratory biomarkers on progression, plasma  
10 
1 
10 
Total 
 
 
152 b 
a All volumes presented are maximums. The actual volume requirements will be detailed in the Laboratory Manual. 
b For efficacy samples up to 2 repeat samples may be required, this would result in 10-20 mL additional blood and bring the maximum total 
to 172 mL. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
100(120) 
7.2 
Handling, storage and destruction of biological samples 
Biological samples for future research may be retained at or on behalf of AstraZeneca for a 
maximum of 25 years following the Last Patient’s Last Visit in the study.  The results from 
future analysis will not be reported in the Clinical Study Report but separately in a Scientific 
Report or Scientific Publication. 
7.2.1 
Pharmacokinetic samples 
Samples will be anonymised by pooling or will be disposed of after the Bioanalytical report 
finalisation or six months after issuance of the draft Bioanalytical report (whichever is earlier), 
unless requested for future analyses. Pooled, anonymised samples may be used for analytical 
method development and/or validation. Anonymised samples will be retained for no more 
than 5 years after the CSR is finalised. Samples may also be disposed of earlier, pending 
further notification. 
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation will not be reported in the Clinical Study 
Report but separately in a Bioanalytical report. 
7.2.2 
Pharmacogenetic samples 
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality.  Samples will be stored for a maximum of 25 
years, from the date of the Last Patient’s Last Visit, after which they will be destroyed.  DNA 
is a finite resource that may be used up during analyses.  Samples will be stored and used until 
no further analyses are possible or the maximum storage time has been reached. 
For all samples irrespective of the type of coding used the DNA will be extracted from the 
blood sample.  The DNA sample will be assigned a unique number replacing the information 
on the sample tube. Thereafter, the DNA sample will be identifiable by the unique DNA 
number only.  The DNA number is used to identify the sample and corresponding data at the 
AstraZeneca genetics laboratories, or at the designated contract laboratory.  No personal 
details identifying the individual will be available to any person (AstraZeneca employee or 
contract laboratory staff working with the DNA.) 
The samples and data for genetic analysis in this study will be single coded.  The link between 
the patient enrolment/randomisation code and the DNA number will be maintained and stored 
in a secure environment, with restricted access WITHIN the Clinical Genotyping Group 
Laboratory Information Management System (LIMS) at AstraZeneca.  The link will be used 
to identify the relevant DNA samples for analysis, facilitate correlation of genotypic results 
with clinical data, allow regulatory audit and to trace samples for destruction in the case of 
withdrawal of consent when the patient has requested disposal/destruction of collected 
samples not yet analysed.  


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
101(120) 
7.3 
Labelling and shipment of biohazard samples 
The Principal Investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria), 
see Appendix C ‘IATA 6.2 Guidance Document.’ 
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the patient unless agreed with AstraZeneca and appropriate 
labelling, shipment and containment provisions are approved. 
7.4 
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle. 
The Principal Investigator at each centre keeps full traceability of collected biological samples 
from the patients while in storage at the centre until shipment or disposal (where appropriate) 
and keeps documentation of receipt of arrival. 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival. 
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers. 
Samples retained for further use are registered in the AstraZeneca biobank system during the 
entire life cycle. 
7.5 
Withdrawal of informed consent for donated biological samples 
If a patient withdraws consent to the use of any optional donated biological samples, the 
samples will be disposed of/destroyed, and the action documented.  If samples are already 
analysed, AstraZeneca is not obliged to destroy the results of this research. 
The Principal Investigator: 
x
Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca 
x
Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented 
x
Ensures the laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed/destroyed, the action 
documented and the signed document returned to the study site 
x
Ensures that the patient and AstraZeneca are informed about the sample disposal. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
102(120) 
AstraZeneca ensures the central and bioanalytical laboratories holding the samples are 
informed about the withdrawn consent immediately and that samples are disposed 
of/destroyed and the action documented and returned to the study site. 
8. 
ETHICAL AND REGULATORY REQUIREMENTS 
8.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples. 
8.2 
Patient data protection 
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation. 
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician or any other third party, unless 
required to do so by law. 
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an investigator might know a patient’s 
identity and also have access to his or her genetic data. Also Regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate. 
8.3 
Ethics and regulatory review 
An Ethics Committee should approve the final study protocol, including the final version of 
the Informed Consent Form and any other written information and/or materials to be provided 
to the patients.  The investigator will ensure the distribution of these documents to the 
applicable Ethics Committee, and to the study site staff. 
The opinion of the Ethics Committee should be given in writing. The investigator should 
submit the written approval to AstraZeneca before enrolment of any patient into the study.  
The Ethics Committee should approve all advertising used to recruit patients for the study. 
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
103(120) 
If required by local regulations, the protocol should be re-approved by the Ethics Committee 
annually. 
Before enrolment of any patient into the study, the final study protocol, including the final 
version of the Informed Consent Form, is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations. 
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities. 
AstraZeneca will provide Regulatory Authorities, Ethics Committees and Principal 
Investigators with safety updates/reports according to local requirements, including SUSARs 
(Suspected Unexpected Serious Adverse Reactions), where relevant. 
In the USA the Principal Investigator is also responsible for providing the Ethics Committee 
with reports of any serious and unexpected adverse drug reactions from any other study 
conducted with the investigational product.  AstraZeneca will provide this information to the 
Principal Investigator. 
Progress reports and notifications of serious and unexpected adverse drug reactions will be 
provided to the Ethics Committee according to local regulations and guidelines. 
8.4 
Informed consent 
The Principal Investigator(s) at each centre will: 
x
Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study 
x
Ensure each patient is notified that they are free to discontinue from the study at any 
time 
x
Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided 
x
Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study 
x
Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File 
x
Ensure a copy of the signed Informed Consent Form is given to the patient 
x
Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the informed consent form that is approved by an Ethics Committee 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
104(120) 
8.5 
Changes to the protocol and informed consent form 
Study procedures will not be changed without the mutual agreement of the International co-
ordinating Investigator and AstraZeneca. 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol). 
The amendment is to be approved by the relevant Ethics Committee and if applicable, also the 
national regulatory authority approval, before implementation.  Local requirements are to be 
followed for revised protocols. 
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s). For distribution to Ethics Committee see Section 8.3. 
If a protocol amendment requires a change to a centre’s Informed Consent Form, AstraZeneca 
and the centre’s Ethics Committee are to approve the revised Informed Consent Form before 
the revised form is used.  
If local regulations require, any administrative change will be communicated to or approved 
by each Ethics Committee. 
8.6 
Audits and inspections 
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification.  The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analysed, and accurately reported according to the protocol, Good Clinical 
Practice (GCP), guidelines of the International Conference on Harmonisation (ICH), and any 
applicable regulatory requirements.  The investigator will contact AstraZeneca immediately if 
contacted by a regulatory agency about an inspection at the centre. 
9. 
STUDY MANAGEMENT BY ASTRAZENECA 
9.1 
Pre-study activities 
Before the first patient is entered into the study, it is necessary for a representative of 
AstraZeneca to visit the investigational study site to: 
x
Determine the adequacy of the facilities 
x
Determine availability of appropriate patients for the study 
x
Discuss with the investigator(s) (and other personnel involved with the study) their 
responsibilities with regard to protocol adherence, and the responsibilities of 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
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AstraZeneca or its representatives.  This will be documented in a Clinical Study 
Agreement between AstraZeneca and the investigator. 
9.2 
Training of study site personnel 
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and the WBDC 
system(s) utilised. 
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. 
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff). 
9.3 
Monitoring of the study 
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to: 
x
Provide information and support to the investigator(s) 
x
Confirm that facilities remain acceptable 
x
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the CRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks 
are being performed 
x
Perform source data verification (a comparison of the data in the CRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent of participating patients. This 
will require direct access to all original records for each patient (eg, clinic charts) 
x
Ensure withdrawal of informed consent to the use of the patient’s biological 
samples is reported and biological samples are identified and disposed of/destroyed 
accordingly, and the action is documented, and reported to the patient 
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct. 
9.3.1 
Source data 
Refer to the Clinical Study Agreement for location of source data. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
106(120) 
9.4 
Study agreements 
The Principal Investigator at each/the centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of patients and in all other respects, not relating to study conduct or treatment of 
patients, the terms of the Clinical Study Agreement shall prevail. 
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled. 
9.4.1 
Archiving of study documents 
The Investigator follows the principles outlined in the Clinical Study Agreement (CSA). 
9.5 
Study timetable and end of study 
The end of the study is defined as ‘the last visit of the last patient undergoing the study.’ All 
patients in this study will be followed for 3 years following their RAI treatment. 
The study is expected to start in 2013 and to end in 2017. 
The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or if recruitment is slow.  AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with selumetinib. 
10. 
DATA MANAGEMENT BY ASTRAZENECA OR DELEGATE 
Data entered in the WBDC system will be immediately saved to a central database and 
changes tracked to provide an audit trail. When the principal investigator has signed the eCRF 
electronically as per eCRF instructions, the subject’s data will be locked. 
Medical coding will be performed using the AstraZeneca Autocoder application.  The Data 
Management Centre Coding Team will perform coding using agreed coding conventions.  
AEs and medical and surgical history will be coded using the standard dictionary – Medical 
Dictionary for Regulatory Activities (MedDRA), and concomitant medication will be coded 
using the AstraZeneca Drug Dictionary. 
SAEs will be entered into a global patient safety database for regulatory reporting purposes 
and be reconciled with the AEs in the clinical database. 
Data associated with biological samples will be transferred to the data manager as an 
electronic file and merged with study data as appropriate. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
107(120) 
Data from external providers (eg, central laboratory) will be validated as appropriate to ensure 
that it is consistent with the clinical data and included in the final database. 
Clean file will be declared for the database once all data have been received, entered, 
validated and all queries resolved.  The database will be locked after clean file has been 
declared.  Treatment codes will not be broken until after clean file.  Following database lock, 
all data will be extracted as SAS (Statistical Analysis Software) data sets for the statistical 
analysis to be performed by AstraZeneca.  
Any genotype data generated in this study will be stored in the AstraZeneca genotyping LIMS 
database, or other appropriate secure system within AstraZeneca and/or third party contracted 
to work with AstraZeneca to analyse samples.  The results from this genetic research may be 
reported in the CSR for the main study, or in a separate report as appropriate. Some or all of 
the clinical datasets from the main study may be merged with the genetic data in a suitable 
secure environment separate from the clinical database.  The results from this genetic research 
will be reported separately from the Clinical Study Report for the main study. 
11. 
EVALUATION AND CALCULATION OF VARIABLES BY 
ASTRAZENECA OR DELEGATE 
11.1 
Calculation or derivation of efficacy variable(s) 
11.1.1 
Complete remission rate at 18 months post-RAI treatment 
Patients will be considered to be in complete remission if they are alive and all of the criteria 
in Section 6.4.1 are met at 18 months post-RAI treatment. 
Complete remission rate at 18 months post-RAI treatment is defined as the proportion of 
patients who have achieved complete remission at this time point. The complete remission 
rate will be calculated using all randomized patients as the denominator.  
11.1.2 
Clinical remission rate at 18 months post-RAI treatment 
Patients will be considered to be in clinical remission if they are alive and all of the criteria in 
Section 6.4.6 are met at 18 months post-RAI treatment. 
Clinical remission rate at 18 months post-RAI treatment is defined as the proportion of 
patients who have achieved clinical remission at this time point. The clinical remission rate 
will be calculated using all randomized patients as the denominator. 
11.1.3 
Thyroid cancer recurrence 
The occurrence and date of any thyroid cancer recurrence will be recorded for patients who 
have previously entered either complete or clinical remission (at any point during the study or 
follow up periods). The rate of thyroid cancer recurrence will be calculated using only patients 
who have achieved remission as the denominator. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
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11.1.4 
Survival status 
The survival status and survival assessment date of all patients will be recorded. Survival time 
will be calculated as the time from the date of randomisation to the date of death. Patients who 
have not died at the time of the final study follow up will be censored at the last date the 
patient was known to be alive. 
11.1.5 
Further therapy 
The dates and type of any further therapy for thyroid cancer will be recorded during the study 
and follow up periods. 
11.2 
Calculation or derivation of safety variable(s) 
11.2.1 
Adverse events 
Adverse events will be listed for each patient and summarised by treatment received according 
to the System Organ Class (SOC) and preferred term assigned to the event using the 
MedDRA.  AEs will be graded according to the National Cancer Institute Common 
Terminology Criteria for AEs Version 4.  The CTC Grade will be assigned by the 
Investigator. 
AE summaries will include all of the following: 
x
Any AEs occurring after commencement of study treatment and within 30 days of 
the last dose of study medication 
x
AEs related to RAI or the combination of RAI and study treatment occurring 
between 30 days after the last dose of study medication and the final study visit at 3 
years following the initial RAI dose 
x
All SAEs occurring after commencement of study treatment until the final study 
visit at 3 years following the initial RAI dose 
AEs occurring before commencement of study treatment will not be included in AE 
summaries but will be included and identified in the patient listings. 
11.2.2 
Other significant adverse events (OAE) 
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and DAEs.  Based on the expert’s judgement, 
significant adverse events of particular clinical importance may, after consultation with the 
Global Patient Safety Physician, be considered OAEs and reported as such in the Clinical 
Study Report.  A similar review of laboratory/vital signs/ECG data will be performed for 
identification of OAEs. 
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction 
or significant additional treatment. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
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11.2.3 
Vital signs, laboratory data, ECGs, ECHO/MUGA, physical examination and 
ophthalmologic examination 
For change from baseline summaries for vital signs, laboratory data, ECGs, and physical 
examination, the baseline value will be the latest result obtained prior to the start of study 
treatment. 
QTcF (Fredericia) will be calculated programmatically by AstraZeneca using the reported 
ECG values (RR and QT). 
QTcF = QT / RR^ (1/3) where RR is in seconds 
The denominator used in laboratory summaries will only include evaluable patients, in other 
words those who had sufficient data to have the possibility of an abnormality. For example: 

If a CTCAE criterion involves a change from baseline, evaluable patients 
would have both a pre-dose and at least 1 post-dose value recorded 

If a CTCAE criterion does not consider changes from baseline, to be 
evaluable the patient need only have 1 post dose-value recorded 
The denominator in vital signs data should include only those patients with recorded data. 
11.3 
Calculation or derivation of PK variables 
The final PK analyses will be the responsibility of Clinical Pharmacology and 
Pharmacometrics, AstraZeneca. 
Using appropriate PK software the available PK data will be used to derive PK parameters 
such as, but not restricted to, Cmax, AUC for Selumetinib, N-desmethyl selumetinib and any 
other metabolites determined. 
The selumetinib, N-desmethyl selumetinib and metabolite concentration-time profiles, along 
with the derived PK variables, will be listed for each patient per dose and dosing day and 
summarised appropriately, as described in the SAP. 
Population PK models may be used to derive the PK parameters and will aim to characterise 
variability in the population by investigating the influence of covariates such as weight, age, 
sex, and/or concomitant medications.  In addition, if the data are suitable, potential 
relationships between plasma selumetinib and N-desmethyl selumetinib concentrations will be 
investigated using a graphical approach and/or appropriate PK/PD modelling techniques.  A 
detailed PK analysis plan will be produced prior to any such investigations and will be 
reported separately. 
11.4 
Calculation or derivation of pharmacogenetic variables 
Genetic data (except BRAF and NRAS data) will be reported separately to the CSR for this 
study. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
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11.5 
Calculation or derivation of biomarker variables  
11.5.1 
Analysis of NRAS and BRAF 
Tumour samples will be collected as outlined in the study plan and assessed for BRAF and 
NRAS mutational status (as detailed in section 6.10.1) to identify patients for this patient 
population. 
11.5.2 
Further biomarker research analysis 
Methods of analysis for all other biomarker research may include investigation of genetic 
variability, gene expression profiling, protein expression profiling. 
12. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
12.1 
Description of analysis sets 
12.1.1 
Intention to treat (ITT) analysis set 
The ITT analysis set will include all randomised patients. The ITT analysis set will be used for 
all efficacy analyses and treatment groups will be compared on the basis of randomised 
treatment, regardless of the treatment actually received. Patients who were randomised but did 
not subsequently go on to receive study treatment will be included in the ITT analysis set. 
12.1.2 
BRAF/NRAS mutation positive analysis set 
For the analysis of the BRAF and NRAS mutation positive population (secondary objective), 
only those patients from the ITT population with genetic samples that are positive for BRAF 
or NRAS will be included. 
12.1.3 
Treatment-compliant (TC) analysis set 
The treatment-compliant analysis set will be a subset of the ITT population containing patients 
that adhered to the minimum study treatment requirements specified in Section 3.1.1, i.e. 
patients who take study treatment twice daily for a minimum of 7 consecutive days prior to 
RAI therapy, on the day of RAI therapy, and for 5 consecutive days afterwards. Patients must 
also have had their RAI dose.  
The TC analysis set will be used as a sensitivity analysis for the primary endpoint. 
12.1.4 
Safety analysis set 
The safety analysis set will consist of all patients who received at least one dose of 
randomised treatment. Safety data will not be formally analysed but summarised using the 
safety analysis set, according to the treatment combination received, ie, erroneously treated 
patients (eg, those randomised to treatment A but actually given treatment B) will be 
summarised according to the treatment they actually received. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
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12.1.5 
PK analysis set 
PK data will be analysed according to treatment received.  This population will comprise all 
patients who receive study treatment as per protocol and do not violate or deviate from the 
protocol in ways that would significantly affect the PK analyses.  The population will be 
defined by the AstraZeneca Study Team Physician, Pharmacokineticist and Statistician prior 
to any analyses being performed. 
12.2 
Methods of statistical analyses 
A comprehensive SAP will be prepared prior to start of recruitment (first subject in).  
Since there is only one primary endpoint/comparison of interest (complete remission rate at 18 
months for selumetinib vs. placebo in the ITT population) the primary endpoint will be 
considered statistically significant if the two-sided p-value is less than 0.05.  
12.2.1 
Complete remission rate at 18 months post-RAI treatment 
The primary endpoint of complete remission rate at 18 months will be compared between 
selumetinib in combination with RAI, and placebo in combination with RAI in the ITT 
population using a logistic regression model including treatment as the only covariate. Results 
will be presented in terms of the odds ratio, 95% confidence interval and associated p-value. A 
sensitivity analysis will be performed using a logistic regression model including treatment 
and adjusted for the covariates histology status (papillary, follicular, poorly differentiated), 
mutation status (BRAF/NRAS positive, BRAF/NRAS not detected) and age, provided there are 
enough data points for a meaningful analysis.  
A secondary analysis of complete remission rate will be performed to compare selumetinib in 
combination with RAI vs. placebo in combination with RAI in the BRAF/NRAS mutation 
positive population using a logistic regression model including treatment as the only covariate.  
A sensitivity analysis will be performed using a logistic regression model adjusted for the 
covariates histology status (papillary, follicular, poorly differentiated) and age, provided there 
are enough data points for a meaningful analysis. 
For the sensitivity analyses using each covariate adjusted logistic regression models, the 
following missing data approach for each covariate will be adopted: 
x
Missing age; impute the mean of observed ages 
x
Missing histology status; add an additional ‘unknown’ category to make 4 
categories (papillary, follicular, poorly differentiated, and unknown) 
x
Missing mutation status; add an additional ‘unknown’ category to make 3 
categories (BRAF/NRAS positive, BRAF/NRAS not detected and unknown) 
The results of the analyses, in terms of treatment effects, will be presented as odds ratios 
together with their associated 95% profile likelihood confidence intervals and 2-sided p-
values. The p-value will be based on twice the change in log-likelihood resulting from the 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
112(120) 
addition of a treatment factor to a model that contains the covariates defined above. The 
complete remission rate and 95% confidence interval will be estimated for each treatment 
arm. 
Sensitivity analyses for the primary endpoint 
The primary endpoint analysis, a logistic regression model including treatment as the only 
covariate for complete remission rate at 18 months, will be repeated:  
x
using the treatment-compliant population. 
x
to allow patients that were identified as being in complete remission outside of the 
specified time windows to be classed as being in complete remission, in order to 
investigate time bias between arms.  
x
excluding patients with high TSH. Elevated TSH can be caused by poor compliance 
and can mean a patient is less likely to achieve remission, therefore this sensitivity 
analysis excludes patients with high TSH, which is defined as a value >10 mIU/L 
recorded at any point by standardised central laboratory analysis. 
Treatment by covariate interactions 
The extent to which the treatment effect is consistent across the subgroups histology status, 
mutation status (ITT population only), gender, race and age will be assessed in the ITT 
population and in the BRAF/NRAS mutation positive population. The presence of a 
quantitative interaction will be assessed by means of an overall global interaction test. This 
will be performed by comparing the fit (likelihood ratio test) of a model including all 
covariate-by-randomised treatment interaction terms, treatment and covariate terms with a 
model that excludes the interaction terms. If the global interaction test is found to be 
statistically significant at the 10% significance level, an attempt to determine the cause and 
type of interaction will be made. Stepwise backward selection will be performed on the 
saturated model, whereby (using a 10% level throughout) the least significant interaction 
terms are removed one-by-one and any newly significant interactions re-included until a final 
model is reached where all included interactions are significant and all excluded interactions 
are non-significant.  Throughout this process all main effects will be included in the model 
regardless of whether the corresponding interaction term is still present.  This approach will 
identify the factors that independently alter the treatment effect and prevent identification of 
multiple correlated interactions. 
For quantitative interactions identified, the presence of any qualitative interactions will be 
assessed using the approach of Gail and Simon (Gail & Simon 1985). For categorical 
covariates the test statistics, based on the appropriate degrees-of-freedom, can be taken 
directly from the paper. For the continuous covariate, the approach will be adapted as follows:  
Identify the cut-point (-E1/E3) of the covariate where the odds ratio for the treatment effect is 
1, where E1 is the treatment parameter estimate and E3 is the treatment-by-covariate parameter 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
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estimate. Re-analyse the data separately for the values of the covariate above and below the 
cut-point and use the separate chi-square values in the Simon and Gail test. 
Subgroup data 
Subgroup data (histology status, BRAF or NRAS mutation status, gender, race and age) will be 
summarised by a forest plot where the odds ratio is plotted on the log scale. For this, age will 
be categorised as d45 or >45 years. The treatment effect and 95% confidence intervals for 
each level of the subgroup will be obtained from a single logistic regression model that 
contains a treatment, factor and treatment-by-factor interaction term.  
12.2.2 
Clinical remission rate at 18 months post-RAI treatment 
The secondary endpoint of clinical remission rate will be analysed as described in Section 
12.2.1, except for primary endpoint specific sensitivity analyses and treatment by covariate 
interaction testing. 
12.2.3 
Thyroid cancer recurrence 
Very few thyroid cancer recurrences are expected on this study, therefore no formal analysis 
of thyroid cancer recurrence data will be performed; data will be listed and summarised.  
12.2.4 
Survival status 
Very few deaths are expected on this study therefore no formal analysis of survival data will 
be performed; data will be listed and summarised. Kaplan-Meier plots of survival may 
produced if appropriate.  
12.2.5 
Further therapy 
No formal analysis of further therapy data will be performed; data will be listed and 
summarised. Kaplan-Meier plots of time to further therapy may produced if appropriate. 
12.2.6 
Safety data analysis 
Safety data will not be formally analysed. All patients who commenced study treatment will 
be included in the assessment of safety and will be summarised by treatment received. 
12.2.7 
PK data analysis 
The selumetinib, N-desmethyl selumetinib and metabolite concentration-time profiles, along 
with the derived PK variables, will be listed for each patient per dose and dosing day and 
summarised appropriately. 
12.2.8 
Genetics 
Any genetic data analysis (other than BRAF and NRAS) will be reported outside the CSR for 
this study. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
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12.2.9 
Biomarker data 
BRAF and NRAS mutation assessment of tumour biopsy will be used to identify patients for 
this primary patient population.  
The results of any other exploratory biomarker investigations will be reported outside of the 
CSR. 
12.2.10 
Interim analyses 
There are no interim analyses planned for this study.  
12.3 
Determination of sample size 
The sample size for this study was selected to be consistent with the research hypothesis as 
described in Section 1.2. 
The primary objective of the study is to compare the efficacy of selumetinib with RAI versus 
placebo with RAI, by assessment of the complete remission rate at 18 months post-RAI 
treatment in the ITT study population. Assuming the true complete remission rates in the 
overall study population are 30% and 50% for the placebo and selumentinib-containing arms, 
respectively, a total of 228 patients, randomised in a 2:1 ratio (152 and 76 patients in the 
selumentinib and placebo-containing arms, respectively) provides at least 80% power to show 
statistical significance, based on a two-sided 5% significance level. 
12.4 
Data monitoring committee  
Due to the short treatment duration in this study there will not be a data monitoring committee 
for this study. 


Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
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13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED 
BY THE INVESTIGATOR 
13.1 
Medical emergencies and AstraZeneca contacts 
The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study. A medical emergency usually 
constitutes an SAE and is to be reported as such, see Section 6.5.4 
In the case of a medical emergency the investigator may contact the Study Delivery Team 
Physician. If the Study Delivery Team physician is not available, contact the Study Delivery 
Team Leader. 
Name  
Role in the study  
Address & telephone number 
 
 
AstraZeneca Physician 
responsible for the protocol at 
central R&D site 
 
 
 
 
 
 
 
 
 
AstraZeneca Study Delivery 
Team Leader responsible for 
the protocol at central R&D 
site 
 
  
  
 
 
 
 
 
24-hour emergency cover at central 
R&D site. 
24-hour emergency cover at 
central R&D site.  
 
 
 
 
13.2 
Overdose  
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the relevant 
AE modules in the CRF and on the Overdose CRF module. 
An overdose without associated symptoms is only reported on the Overdose CRF module. 
If an overdose on an AstraZeneca study drug occurs in the course of the study, then 
investigators or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
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Clinical Study Protocol 
Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
116(120) 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site. 
For overdoses associated with SAE, standard reporting timelines apply, see Section 6.5.4.  For 
other overdoses, reporting should be done within 30 days. 
13.3 
Pregnancy 
All outcomes of pregnancy should be reported to AstraZeneca. 
13.3.1 
Maternal exposure 
If a subject becomes pregnant during the course of the study, investigational product should be 
discontinued immediately. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication.  Congenital abnormalities/birth defects and spontaneous 
miscarriages should be reported and handled as SAEs.  Elective abortions without 
complications should not be handled as AEs.  The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should be followed up and documented even if the subject was discontinued from the study. 
If any pregnancy occurs in the course of the study, then investigators or other site personnel 
inform appropriate AstraZeneca representatives immediately, or no later than 24 hours of 
when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
days for SAEs, see Section 6.5.4 and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is used 
to report the outcome of the pregnancy. 
13.3.2 
Paternal exposure 
The outcomes of any conception occurring from the date of the first dose, until 30 days after 
last dose, must be followed up and documented in the “Pregnancy Outcome Report” form. 
Male patients must refrain from fathering a child for 12 weeks following the last dose of study 
treatment, since the potential for chromosomal aberrations in male gametes, and possible 
teratogenic effects thereof, has not yet been thoroughly investigated. Restrictions from 
fathering children should also take into account local recommendations following therapy 
with RAI. 


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Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
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Pregnancy of the patients’ partner is not considered to be an AE.  However, the outcome of all 
pregnancies (including spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented. 
14. 
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Chakravarty D et al 2011  
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Cooper et al 2009 
Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association 
Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid 
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De Vita et al, 2005 
De Vita G, Bauer L, da Costa VM, De Felice M, Baratta MG, De Menna M, Di Lauro R. 
Dose-dependent inhibition of thyroid differentiation by RAS oncogenes. Mol Endocrinol. 
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Durante et al 2006 
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Durante et al 2007 
Durante C et al., MRAF Mutations in papillary thyroid carcinomas inhibit gene involved in 
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Espadinha et al 2009 
Espadinha C et al., Expression of iodine metabolism genes in human thyroid tissue: evidence 
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Franco A et al. 2011 
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Maraise R, Davies T, Weinsteing L, Cheng M, Rosen N, Ghossein R, Knauf J, and Fagin J. 


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Drug Substance Selumetinib (AZD6244)  
Study Code D1532C00065 
Edition Number 4 
Date 01 July 2014 
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Thyrotrophin receptor signaling dependence of Braf-induced thyroid tumour initiation in 
mice.  PNAS, 2011;108(4) 1615-1620. 
Gail & Simon 1985 
Gail M & Simon R. Testing for qualitative interactions between treatment effects and subject 
subsets. Biometrics 1985;41: 261-372. 
Hayes et al 2012 
Hayes DN, Lucas AS, Tanvetyanon T, Kryzanowska MK, Chung CH, Murphy BA, et al. 
Phase II efficacy and pharmacogenomic study of selumetinib (AZD6244; ARRY-142886) in 
iodine131-refractory papillary thyroid carcinoma with or without follicular elements. Clin 
Cancer Res 2012;18(7): 2056-2065. 
Ho et al 2012 
Reacquisition Of RAI Uptake Of RAI-Refractory Metastatic Thyroid Cancers By Pre-
treatment With The Selective MEK Inhibitor selumetinib: A Pilot Study. J Clin Oncol 30, 
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Kimura et al 2003 
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Clinical Study Protocol Appendix G 
 
Drug Substance 
Selumetinib (AZD6244) 
 
Study Code 
D1532C00065 
 
Edition Number 
2 
 
Date 
01 July 2014 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix G 
Guidance for Management of Adverse Events in Studies of Selumetinib  
 


Clinical Study Protocol Appendix G 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065  
Edition Number 2 
Date 01 July 2014 
2(10) 
TABLE OF CONTENTS 
PAGE
 
TABLE OF CONTENTS.........................................................................................2 
1. 
GUIDANCE FOR THE MANAGEMENT OF PATIENTS WITH RASH ............3 
2. 
GUIDANCE FOR MANAGEMENT OF VISUAL SYMPTOMS OR 
ABNORMAL FINDINGS.......................................................................................5 
3. 
RECOMMENDATIONS FOR DIARRHOEA MANAGEMENT..........................6 
3.1 
Initial management of uncomplicated Grade 1 or 2 diarrhoea.................................7 
3.2 
Management of persistent (>24h) Grade 1 or 2 diarrhoea despite 
loperamide at high dose ...........................................................................................7 
3.3 
Management of any grade uncontrolled or complicated diarrhoea, or Grade 
3-4 diarrhoea ............................................................................................................7 
4. 
GUIDANCE FOR MANAGEMENT OF PATIENTS WITH DYSPNOEA ........10 
 LIST OF TABLES 
Table 1 
Example topical steroids and antibiotics (use according to local 
guidelines) ..................................................................................................4 
Table 2 
CTCAE (version 4) grading for diarrhoea..................................................6 
 LIST OF FIGURES 
Figure 1 
Guidance for the management of patients with diarrhoea..........................9 
 


Clinical Study Protocol Appendix G 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065  
Edition Number 2 
Date 01 July 2014 
3(10) 
1. 
GUIDANCE FOR THE MANAGEMENT OF PATIENTS WITH 
RASH 
 
‡ selumetinib or matching placebo 
Version: Final 2.0 28Sep2012 


Clinical Study Protocol Appendix G 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065  
Edition Number 2 
Date 01 July 2014 
4(10) 
Table 1 
Example topical steroids and antibiotics (use according to local 
guidelines) 
Topical steroids moderate strength 
 
Triamcinolone acetonide 0.025% 
Fluticasone proprionate 0.05% 
Desonide 0.05% 
Aclometasone 0.05% 
Topical antibiotics 
Clindamycin 1 - 2% 
 
 
Metronidazole 1% 
 
  
Erythromycin 1% - 2% 
Silver sulphadiazine 1%   
Oral antibiotics 
Doxycycline 100 mg bd 
Minocycline 100 mg bd 
Oxytetracycline 500 mg bd 


Clinical Study Protocol Appendix G 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065  
Edition Number 2 
Date 01 July 2014 
5(10) 
2. 
GUIDANCE FOR MANAGEMENT OF VISUAL SYMPTOMS 
OR ABNORMAL FINDINGS 
 
 
 
 


Clinical Study Protocol Appendix G 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065  
Edition Number 2 
Date 01 July 2014 
6(10) 
3. 
RECOMMENDATIONS FOR DIARRHOEA MANAGEMENT 
Diarrhoea may occur during treatment with selumetinib (AZD6244) and action should be 
taken as soon as symptoms develop.  The recommendations for diarrhoea management are 
based on guidelines from the American Society of Clinical Oncology (J Clin Oncol 2004; 
22:2918-26).  These guidelines recommend that treatment-induced diarrhoea should be 
carefully monitored and treated aggressively to ensure that severe complications are avoided 
and that treatment is not delayed.  
x
Patients should be made aware that they may experience diarrhoea and be 
encouraged to record the number of stools and report possible associated symptoms 
x
Patients should be given loperamide (in accordance with local regulation and local 
practice) to take home with them and be advised to start immediately after the first 
episode of unformed stool. 
x
Patients should be given dietary advice in case of diarrhoea (eg. BRAT [bananas, 
rice, apple sauce, toast, plain pasta] diet; readily digestible food; avoidance of 
lactose-containing products, fried, fatty or spicy food) and increase fluid intake (8 to 
10 glasses of clear fluids daily, including water and fluids containing salt and sugar, 
such as sports drinks and clear broth). 
x
Patients should seek advice early, from their physician or study nurse, if: 
(a) 
Persistent Grade 1 or 2 diarrhoea (refer to Section 3.2), or 
(b) 
Grade 3 or 4 diarrhoea, or 
(c) 
Diarrhoea becomes complicated by associated vomiting or inability to take 
oral fluids; marked abdominal distension or cramping; bloody stools, fever or 
symptoms of hypotension. 
Table 2 
CTCAE (version 4) grading for diarrhoea 
CTCAE 
Grade 
Patients without colostomies 
Patients with colostomies 
Grade 1 
Increase in number of stools per 
day (<4) 
Mild increase in loose watery colostomy output 
compared with pre-treatment 
Grade 2 
Increase in number of stools per 
day (4-6) or nocturnal episodes 
Moderate increase in loose watery colostomy 
output compared with pre-treatment, not 
interfering with normal activity 
Grade 3 
Increase of more than 7 stools per 
day or incontinence or needing 
support for dehydration.   
Severe increase in loose watery colostomy output 
compared with pre-treatment and interfering with 
normal activity 


Clinical Study Protocol Appendix G 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065  
Edition Number 2 
Date 01 July 2014 
7(10) 
Table 2 
CTCAE (version 4) grading for diarrhoea 
CTCAE 
Grade 
Patients without colostomies 
Patients with colostomies 
Grade 4 
Life-threatening consequences (eg,  hemodynamic collapse) 
 
3.1 
Initial management of uncomplicated Grade 1 or 2 diarrhoea  
x
Patients should immediately start loperamide after the first episode of diarrhoea 
(4 mg initially) and continue loperamide (2 mg every 4 hours or after each 
unformed stool) until they have been free from diarrhoea for at least 12 hrs 
x
If after 12 hours of loperamide treatment the diarrhoea is not improving or resolved, 
the patient should be instructed to contact the centre and to increase to high dose 
loperamide (2 mg every 2 hours, or 4 mg every 4 hours at night) and continue to 
take loperamide until they have been free from diarrhoea for at least 12 hrs.  
Additional treatment may be considered according to local practice. 
3.2 
Management of persistent (>24h) Grade 1 or 2 diarrhoea despite 
loperamide at high dose 
The patient should be seen by the physician or study nurse for full evaluation and the 
following should be considered: 
x
Rehydration and electrolytes replacement as appropriate 
x
Infectious causes and aetiologies such as Clostridium difficile or viral 
gastroenteritis; 
x
Antibiotics if appropriate (for example an oral fluroquinolone for 7 days) 
particularly if the patient is neutropenic (<1 x 109/L) or has a fever; 
x
Discontinuation of loperamide and start of octreotide (Sandostatin); 
It may also be appropriate to consider: 
x
Addition of other second-line anti-diarrhoeal agents according to local practice 
x
Selumetinib (or matching placebo) interruption until resolution of the diarrhoea 
x
Hospitalisation  
3.3 
Management of any grade uncontrolled or complicated diarrhoea, 
or Grade 3-4 diarrhoea 
x
Hospitalisation and full evaluation,  


Clinical Study Protocol Appendix G 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065  
Edition Number 2 
Date 01 July 2014 
8(10) 
x
Intravenous fluids, electrolytes and antibiotics if needed (eg. fluroquinolone) 
x
Interrupt selumetinib (or matching placebo) until diarrhoea and associated 
symptoms resolve 
x
Start octreotide (Sandostatin). 
x
In studies involving combination of selumetinib (or matching placebo) with other 
anti-cancer treatment, interruption or delay of the combination agent may be 
considered according to manufacturer’s guidance or local practice. 


Clinical Study Protocol Appendix G 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065  
Edition Number 2 
Date 01 July 2014 
9(10) 
Figure 1  
Guidance for the management of patients with diarrhoea 
Diarrhoea
CTC Grade 1 or 2 
uncomplicated diarrhoea
Loperamide : 4mg initially
then 2mg every 4 hours or
after each unformed stool
Dietary management
Diarrhoea resolving or
resolved after 12hrs of
loperamide treatment
Continue loperamide for 12 
hours after diarrhoea
resolved
Adjust diet
Persistent diarrhoea not
resolved after 12 hours of
loperamide and remains 
uncomplicated CTC Grade 1
or 2
Patient should: Contact the
centre and increase to high
dose loperamide (2mg every 2 
hours; possibly 4mg every 4hrs
at night)
Additional treatment may be
considered according to local
practice
Diarrhoea resolving or 
resolved after 24 hours of 
high dose loperamide
treatment
Continue loperamide for 12 
hours after diarrhoea 
resolved 
Adjust diet 
Persistent diarrhoea not 
resolved after 24 hours of 
high dose loperamide
Full examination.   
Treat as per local practices. 
(Rehydration, electrolytes, 
octreotide, antibiotics, 
hospitalisation). Consider 
selumetinib
‡  
dose interruption ** 
CTC Grade 1 or 2
complicated diarrhoea* and 
CTC Grade 3 or 4 at any 
time
Hospitalisation 
Treat as per local practices 
(iv rehydration, electrolytes, octreotide, 
iv antibiotics). 
Selumetinib
‡ dose interruption** 
 
 
 
*Diarrhoea becomes complicated by associated vomiting or inability to take oral fluids; marked abdominal 
distension or cramping; bloody stools, fever or symptoms of hypotension 
**Consider interruption or delay of combination anticancer agent if applicable 
‡ selumetinib or matching placebo 
Document version: Final 2.0 28Sept2012 


Clinical Study Protocol Appendix G 
Drug Substance Selumetinib (AZD6244) 
Study Code D1532C00065  
Edition Number 2 
Date 01 July 2014 
10(10) 
4. 
GUIDANCE FOR MANAGEMENT OF PATIENTS WITH 
DYSPNOEA 
 
 

SAP_001.pdf: 
Statistical Analysis Plan
Study Code
D1532C00065
Edition Number
4.0
Date
04 APR 2018
A Randomised, Double Blind Study to Compare the Complete Remission 
Rate Following a 5-Week Course of Selumetinib or Placebo and Single Dose 
Adjuvant Radioactive Iodine Therapy in Patients with Differentiated 
Thyroid Cancer


Statistical Analysis Plan 
Study Code D1532C00065
Edition Number 4.0
Date 04 APR 2018
2
A Randomised, Double Blind Study to Compare the Complete Remission 
Rate Following a 5-Week Course of Selumetinib or Placebo and Single Dose
Adjuvant Radioactive Iodine Therapy in Patients with Differentiated 
Thyroid Cancer
Study Statistician
Date
PPD


Statistical Analysis Plan 
Study Code D1532C00065
Edition Number 4.0
Date 04 APR 2018
3
A Randomised, Double Blind Study to Compare the Complete Remission 
Rate Following a 5-Week Course of Selumetinib or Placebo and Single Dose 
Adjuvant Radioactive Iodine Therapy in Patients with Differentiated 
Thyroid Cancer
Global Product Statistician
Date
PPD


Statistical Analysis Plan 
Study Code D1532C00065
Edition Number 4.0
Date 04 APR 2018
4
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
SIGNATURE OF STUDY STATISTICIAN........................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN ..................................3
TABLE OF CONTENTS.....................................................................................4
1.
STUDY DETAILS.............................................................................................10
1.1
Study objectives................................................................................................. 10
1.1.1
Primary objective...............................................................................................10
1.1.2
Secondary objectives..........................................................................................10
1.1.3
Exploratory objectives ....................................................................................... 10
1.2
Study design ...................................................................................................... 11
1.3
Number of subjects ............................................................................................11
2.
ANALYSIS SETS .............................................................................................12
2.1
Definition of analysis sets .................................................................................. 12
2.1.1
Intention to treat (ITT) analysis set.....................................................................12
2.1.2
BRAF/NRAS mutation positive analysis set.......................................................12
2.1.3
Treatment-compliant (TC) analysis set...............................................................12
2.1.4
Safety analysis set..............................................................................................12
2.1.5
Pharmacokinetic (PK) analysis set......................................................................12
2.2
Important deviations .......................................................................................... 13
2.2.1
Important Inclusion Criteria Deviations..............................................................14
2.2.2
Important Exclusion Criteria Deviations.............................................................15
2.2.3
Important Investigational Treatment Deviations.................................................15
2.2.4
Important Prohibited Concomitant Medication Deviations .................................15
2.2.5
Important Protocol-required Procedures Deviations............................................15
3.
PRIMARY AND SECONDARY VARIABLES.................................................16
3.1
General principles.............................................................................................. 16
3.1.1
Study Day..........................................................................................................16
3.1.2
Visit Windows ...................................................................................................16
3.1.3
Handling of missing data.................................................................................... 17
3.2
Efficacy variables...............................................................................................17
3.2.1
Complete remission rate at 18 months post-RAI treatment .................................17
3.2.2
Clinical remission rate at 18 months post-RAI treatment....................................20
3.2.3
Visit windows for complete and clinical remission assessment...........................22
3.3
Safety variables.................................................................................................. 22


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3.3.1
Adverse events (AE) .......................................................................................... 22
3.3.2
Vital signs, laboratory data, ECGs, ECHO/MUGA, physical examination 
and ophthalmologic examination........................................................................23
3.4
PK data.............................................................................................................. 23
3.5
Other data .......................................................................................................... 24
3.5.1
Thyroid cancer recurrence..................................................................................24
3.5.2
Survival status....................................................................................................24
3.5.3
Further therapy...................................................................................................24
4.
ANALYSIS METHODS....................................................................................24
4.1
General principles.............................................................................................. 24
4.2
Analysis methods...............................................................................................25
4.2.1
Primary analysis.................................................................................................27
4.2.2
Secondary analyses ............................................................................................28
4.2.3
Sensitivity analyses............................................................................................ 28
4.2.3.1
Logistic regression model including treatment and adjusted for covariates ......... 28
4.2.3.2
Additional sensitivity analyses ........................................................................... 30
4.2.4
Subgroup Treatment Effects...............................................................................30
4.2.5
Demographic and baseline characteristics .......................................................... 32
4.2.6
Safety.................................................................................................................32
4.2.6.1
Adverse events...................................................................................................32
4.2.6.2
Vital signs, laboratory data, ECGs, ECHO/MUGA, physical examination 
and ophthalmologic examination........................................................................33
4.2.7
Other analyses.................................................................................................... 33
4.2.7.1
Thyroid cancer recurrence..................................................................................33
4.2.7.2
Survival status....................................................................................................33
4.2.7.3
Further therapy...................................................................................................33
4.2.7.4
PK .....................................................................................................................34
4.2.7.5
Genetics.............................................................................................................34
4.2.7.6
Biomarker data................................................................................................... 34
5.
INTERIM ANALYSES – NOT APPLICABLE .................................................34
6.
CHANGES OF ANALYSIS FROM PROTOCOL .............................................34
7.
REFERENCES ..................................................................................................35
LIST OF TABLES
Table 1
Programmatic derivation of complete remission status ..........................19
Table 2
Programmatic derivation of clinical remission status.............................21
Table 3
Statistical analyses and pre-planned sensitivity analyses........................25


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Edition Number 4.0
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Table 4
Data specification for variables in logistic regression models 
and/or subgroup analyses ......................................................................29


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Edition Number 4.0
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LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
AE
Adverse Event
BRAF
v-raf murine sarcoma viral oncogene homolog B1
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Event
DAE
Discontinuation of Investigational Product due to Adverse Event
DNA
Deoxyribonucleic acid
DTC
Differentiated Thyroid Cancer
ECG
Electrocardiogram
ECHO
Echocardiogram
FNA
Fine Needle Aspiration
IM
Intramuscular
ITT
Intention To Treat
LLOQ
Lower Limit Of Quantification
MRI
Magnetic Resonance Imaging
MTP
Multiple Testing Procedure
MUGA
Multi Gated Acquisition Scan
NRAS
Neuroblastoma RAS viral (v-ras) oncogene homolog
OAE
Other Adverse Event
PK
Pharmacokinetics
PR(PQ)
ECG interval measured from the beginning of the P wave to the beginning 
of the Q wave (or the R wave in the absence of Q wave).  PR (PQ) 
represents the time interval from start of a trial depolarisation to the start of 
ventricular depolarisation.
QRS
Interval on the ECG from the start of ventricular electrical activation of the 
heart to the J point, with start taken as start of Q wave or R wave (when a Q 
wave is missing); the time interval of ventricular depolarisation.
QT
ECG interval measured from the beginning of the Q wave (or the R wave if 
Q is missing) to the end of the T wave; the time interval of ventricular 
depolarisation and repolarisation.
QTcF
Corrected Qt interval according to Fredericia’s formula
RAI
Radioactive Iodine (131I)


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Edition Number 4.0
Date 04 APR 2018
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Abbreviation or 
special term
Explanation
rhTSH
Recombinant human Thyroid Stimulating Hormone
RR
The time between corresponding points on 2 consecutive R waves on ECG; 
the interval from one ventricular depolarisation to the next
SAE
Serious Adverse Event
SAS
Statistical Analysis Software
SOC
System Organ Class
TSH
Thyroid Stimulating Hormone
ULOQ
Upper Limit of Quantification
US
Ultrasound
WBS
Whole Body Scintigraphy


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Study Code D1532C00065
Edition Number 4.0
Date 04 APR 2018
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AMENDMENT HISTORY
Date
Brief description of change
03 April 2018
Updated list of protocol violations
Updated efficacy variables to indicate that any abnormalities seen in 
US, CT or MRI unless confirmed by FNA/biopsy will be considered 
benign.
Added that a separate document to describe the algorithmic steps to 
determine the biochemical, clinical and complete remission status of 
each patient based on CSP will be provided by AZ to the designee.
Updated the analysis windows for biochemical, clinical and complete 
remission to include patients that had any part the composite endpoint 
assessment for Stage 1 (suppressed Tg, TgAb, US and/or 
FNA/Biopsy) evaluated before 75 weeks (i.e. prior to 525 days) post 
RAI-treatment and the remaining composite endpoint assessments for 
Stage 2 (stimulated Tg, WBS) and Stage 3 (CT and MRI) evaluated at 
least 75 weeks (525 days) post RAI-treatment, in the derivation of 
biochemical, clinical and complete remission.
Added sensitivity analysis on complete remission to include patients 
as per the CSP window. 
Updated the analysis to indicate that the two-sided p-value will be 
based on profile likelihood. 
23SEP2016
Updated Tables 1 and 2 to match CSP.
Updated the analysis windows to include patients that composite 
endpoint assessments for Stage 1, Stage 2 (stimulated Tg, WBS) and 
Stage 3 (CT and MRI) evaluated at least 75 weeks (525 days) post 
RAI-treatment, in the derivation of biochemical, clinical and 
complete remission. 
Removed the requirement that all necessary primary endpoint 
assessments must be completed within a 8 week period.
Added description of outputs needed for demographic and baseline 
characteristics.


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Edition Number 4.0
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1. STUDY DETAILS
1.1
Study objectives
1.1.1
Primary objective
!
To compare the efficacy of selumetinib with radioactive iodine therapy (RAI), 
versus placebo with RAI, by assessment of complete remission rate at 18 months 
post RAI treatment in the intention to treat (ITT) study population.  Complete 
remission is defined in Section 3.2.1.
1.1.2
Secondary objectives
!
To compare the efficacy of selumetinib with RAI, versus placebo with RAI, by 
assessment of complete remission rate at 18 months post RAI treatment in a sub-
group of patients with tumours known to be mutation positive for v-raf murine 
sarcoma viral oncogene homolog B1 (BRAF) or neuroblastoma RAS viral (v-ras) 
oncogene homolog (NRAS).  Complete remission is defined in Section 3.2.1.
!
To compare the efficacy of selumetinib with RAI, versus placebo with RAI by 
assessment of clinical remission rate at 18 months post RAI treatment in the overall 
study population.  Clinical remission is defined in section 3.2.2.
!
To compare the efficacy of selumetinib with RAI, versus placebo with RAI by 
assessment of clinical remission rate at 18 months post RAI treatment in a sub-
group of patients with tumours known to be mutation positive for BRAF or NRAS.  
Clinical remission is defined in section 3.2.2.
!
To assess the safety and tolerability of selumetinib with RAI compared to placebo 
with RAI.
!
To investigate the pharmacokinetics (PK) of selumetinib and N-desmethyl 
selumetinib when administered to patients with differentiated thyroid cancer.
1.1.3
Exploratory objectives
!
To explore subsequent thyroid cancer therapy given to patients who receive 
selumetinib with RAI, or placebo with RAI.
!
To investigate the relationship between selumetinib and/or N-desmethyl selumetinib 
plasma concentrations/exposure and clinical outcomes, efficacy, AEs and/or safety 
parameters.
!
To collect tumour, plasma and serum samples for potential future research on 
biomarkers relevant to Differentiated Thyroid Cancer (DTC) and response and 
resistance to study treatments.


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Edition Number 4.0
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!
To collect and store DNA for future exploratory research into genes/genetic 
variation that may influence response (ie, distribution, safety, tolerability and 
efficacy) to selumetinib or RAI and/or susceptibility to cancer.
1.2
Study design
This is a double-blind, randomised, placebo-controlled, multi-centre study comparing the 
efficacy of a short course (approximately 5 weeks) of selumetinib (75 mg, orally twice daily) 
with adjuvant RAI, to placebo with RAI.  
Following recovery from surgery (1 or 2-stage total thyroidectomy), and screening to 
determine study eligibility, patients will be randomised and will take their assigned study 
treatment (selumetinib or placebo) twice daily for a period of approximately 5 weeks.   Study 
treatment will begin approximately 4 weeks prior to the planned day of single dose RAI 
therapy, and will be continuous until 5 days following RAI therapy.   Patients will be required 
to adhere to a standardised low iodine diet prior to their RAI therapy.   For each of the 2 days 
immediately prior to their planned RAI therapy, patients will receive a 0.9 mg intramuscular 
(IM) recombinant human TSH injection (rhTSH, Thyrogen), in order to stimulate iodide 
uptake (patients or clinicians choosing to prepare for RAI ablation by withdrawal of thyroid 
hormone treatment will be ineligible for this study).   Following the 2 consecutive days of 
rhTSH injections, patients will receive their planned RAI therapy as a fixed single 100 mCi 
(3.7 GBq) dose of 131I the immediate next day.  Study treatment will be taken as normal on the 
day of RAI therapy, and will be discontinued 5 days following the patient’s RAI therapy.
Following RAI therapy, each patient will be followed up for a period of 18 months until the 
primary endpoint assessment of complete remission.  The biochemical analysis contributing to 
the 18 month primary endpoint of complete remission will be performed by standardised 
central methodology, and the radiological imaging (Whole Body Scintigraphy (WBS), 
Computed Tomography (CT), and Magnetic Resonance Imaging (MRI)) contributing to the 
18 month primary endpoint assessment will be subject to a blinded independent central 
review to minimise the risk of bias. Additional thyroid cancer therapy (eg, surgery or RAI 
treatment) must only be given during the 18 month primary endpoint follow up period 
according to the pre-specified study re-treatment criteria (see protocol Section 5.9 for details).  
Patients who do receive re-treatment in the 18 months following their initial RAI therapy, will 
not have any 18 month primary endpoint assessments performed, though they will be included 
in the ITT population (as not being in remission) and they will remain in the study and enter 
standard of care follow up according to local practice.
Following the primary endpoint assessments (or re-treatment), all randomised patients will be 
further followed-up at least 3 years following their initial RAI treatment.
1.3
Number of subjects
The primary objective of this study is to compare the efficacy of selumetinib with RAI, versus 
placebo with RAI, by assessment of the complete remission rate at 18 months post RAI 
treatment in the ITT study population.


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Patients will be randomised into this study in a 2:1 ratio.  Assuming the true complete 
remission rates in the overall study population are 30% and 50% for the placebo and 
selumetinib-containing arms, respectively, 228 patients (152 and 76 patients randomised to the 
selumetinib and placebo-containing arms, respectively) provides at least 80% power to 
demonstrate a statistically significant difference at the 5% (2-sided) significance level.
2.
ANALYSIS SETS
2.1
Definition of analysis sets
2.1.1
Intention to treat (ITT) analysis set
The ITT analysis set will include all randomised patients.  The ITT analysis set will be used 
for all efficacy analyses and treatment arms will be compared on the basis of randomised 
treatment, regardless of the treatment actually received.  Patients who were randomised but 
did not subsequently go on to receive study treatment will be included in the ITT analysis set.
2.1.2
BRAF/NRAS mutation positive analysis set
For the analysis of the BRAF and NRAS mutation positive population (secondary objective), 
only those patients from the ITT population with genetic samples that are positive for BRAF
or NRAS will be included.  Treatment arms will be compared on the basis of randomised 
treatment, regardless of the treatment actually received.
2.1.3
Treatment-compliant (TC) analysis set
The treatment-compliant analysis set will be a subset of the ITT population containing patients 
that adhered to the minimum study treatment requirements specified in Section 3.1.1 of the 
protocol, i.e. patients who take study treatment twice daily for a minimum of 7 consecutive 
days prior to RAI therapy, on the day of RAI therapy, and for 5 consecutive days afterwards.  
Patients must also have had their RAI dose.
The TC analysis set will be used as a sensitivity analysis for the primary endpoint.  
2.1.4
Safety analysis set
The safety analysis set will consist of all patients who received at least one dose of 
randomised treatment.  Safety data will not be formally analysed but summarised using the 
safety analysis set according to the treatment combination received, i.e., erroneously treated 
patients (e.g., those randomised to treatment A but actually given treatment B) will be 
summarised according to the treatment they actually received.
2.1.5
Pharmacokinetic (PK) analysis set
PK data will be analysed according to treatment received.   This population will comprise all 
patients where at least one PK concentration has been generated and who receive study 
treatment as per protocol and do not violate or deviate from the protocol in ways that would 
significantly affect the PK analyses.  The population will be further defined by the 


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AstraZeneca Study Team Physician, Pharmacokineticist and Statistician prior to breaking of 
the blind for any analyses being performed.
2.2
Important deviations
Important deviations are defined as deviations that could impact the interpretation of study 
data.  Important deviations will be listed and summarised by randomised treatment group. 
Patients randomised but not dosed (with selumetinib/placebo) will lead to exclusion from the 
Safety analysis set. None of the other deviations will lead to patients being excluded from any 
of the analysis sets described in Section 2.1 (with the exception of the PK analysis set, if the 
deviation is considered to impact upon PK). A per-protocol analysis excluding patients with 
significant protocol deviations is not planned.
If the deviations are serious enough to have the potential to impact the primary analysis, 
sensitivity analyses may be performed. Some deviations may be important from safety point 
of view but these may not affect the interpretation of the study results.
A list of important protocol deviations are defined in sections 2.2.1, 2.2.2, 2.2.3, 2.2.4. Note 
that the contents of these sections are not an exhaustive list. The study team physician and 
statistician will identify, adjudicate and classify a complete list of important deviations from 
monitor reports and programmatic checks prior to database lock and unblinding.


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2.2.1
Important Inclusion Criteria Deviations
Inclusion Criteria
Description
03
Subject without histologically or cytologically confirmed follicular 
cell derived differentiated thyroid cancer including papillary thyroid 
cancer and all variants, follicular thyroid cancer and all variants, and 
poorly differentiated thyroid cancer.
05
Subject not presenting at least one of the following staging categories 
post-surgery: 
a) Primary tumour greater than 4 cm 
b) Primary tumour of any size with gross extrathyroidal extension 
outside the thyroid gland (T4 disease) 
c) N1a or N1b disease with at least 1 lymph node ≥ 1 cm 
d) N1a or N1b disease involving 5 or more lymph nodes (of any size)
06
Subject has not had a one or two-stage total thyroidectomy with 
therapeutic neck dissection of any clinically apparent metastatic 
lymph nodes (levels I to VII of the lateral and central neck) and all 
known tumour has not been resected. 
For Subject who has had a two-stage thyroidectomy, the second 
surgical procedure has taken place more than 12 weeks after the first 
procedure. 
Subject having undergone a robotic or endoscopic thyroidectomy, or 
any other novel or remote access surgical technique. 
07
Subject had all of the following post-operative assessments performed 
sooner than 4 weeks post-surgery (post their last surgery if it was a 2-
stage thyroidectomy): 
a) Neck US exam 
b) Neck MRI with contrast 
c) Chest CT without contrast 
Results from at least one of below assessments did not confirm the 
absence of macroscopic disease: 
a) Neck US exam 
b) Neck MRI with contrast 
c) Chest CT without contrast 
08
Subject not suitable for radioactive iodine therapy. 
09
Subject not suitable for TSH suppression with a goal of ≤0.5 mIU/L 
TSH for the duration of the study 
10
Subject is not willing and able to start study treatment within 6-16 
weeks after thyroid cancer surgery (last surgery if it was a 2-stage 
thyroidectomy). 
11
WHO or ECOG Performance Status not 0 or 1. 


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2.2.2
Important Exclusion Criteria Deviations
Exclusion 
Criteria
Description
01
Known distant metastatic disease at study entry. 
02
Diagnosis of anaplastic thyroid cancer, medullary thyroid cancer, or 
Hürthle cell carcinoma (apart from Hürthle variant with oncocytic 
cells having the nuclear features of papillary carcinoma). 
03
Presence of anti-Tg antibodies at screening 
04
Previous treatment with 131I (RAI) or external beam radiation therapy 
(EBRT) at any time in the past. 
06
Subject has received an investigational drug during the last 4 weeks 
prior to first dose of study treatment. 
08
Subject not willing to use rhTSH prior to their RAI treatment. 
18
History of another primary malignancy within 5 years prior to starting 
study treatment, except for adequately treated basal or squamous cell 
carcinoma of the skin or cancer of the cervix in situ and the disease 
under study. 
21
Previous treatment with any MEK or BRAF inhibitor. 
22
Previous enrolment or treatment in the present study. 
2.2.3
Important Investigational Treatment Deviations
Description
Study medication is not administered according to the CSP 
Received wrongly randomized treatment. 
Compliance rate less than 80% (less than 4 weeks or 28 days). 
2.2.4
Important Prohibited Concomitant Medication Deviations
Description
Subject received other anti-cancer agents, or investigational drugs whilst receiving study 
medication or during follow-up in this study (not including scenario when the patient 
withdraws from the study, or meets the re-treatment criteria). 
2.2.5
Important Protocol-required Procedures Deviations
Description


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Therapeutic RAI dose (131I) administered not according to CSP [100 mCi (3.7 GBq) 131I 
(+/- 10% at the time of administration)] 
Diagnostic WBS dose (131I) administered not according to CSP [5 mCi (185 MBq) 131I 
(+/- 10% at the time of administration)]
Visit procedures of Visit 10/Month 18 - primary endpoint not performed within the visit 
window and/or assessment window defined in the SAP. 
Visit procedures of Visit 10/Month 18 - primary endpoint not done according to the 
description in the CSP 
e.g.: 
- missing central lab testing for TgAb and/or Tg 
- rhTSH injection not administered on two consecutive days (Day 1 and Day 2) 
- Diagnostic RAI administration not 2 days prior to the WBS (either Day 2 or Day 3) 
- missing central lab testing result for stimulated Tg (Day 5 of rhTSH injection) 
- missing US 
- missing biopsy with positive US results of lesion >= 5 mm
- missing chest CT and/or neck MRI 
3.
PRIMARY AND SECONDARY VARIABLES
3.1
General principles
Unless otherwise stated, baseline will be defined as the last available measurement prior to 
dosing with study treatment.  For laboratory data and vital signs data, pre-dose assessments 
will be performed at screening.
Unless otherwise specified, data summaries and listings will be presented by the initial 
treatment arm a patient was assigned to, i.e., initial randomised treatment.
3.1.1
Study Day
In some cases, where data is summarised over time, study day will be calculated based on the 
actual assessment date.   Efficacy data will be summarised using the ITT analysis set, so study 
day is derived in relation to the date of randomisation (study day 1 for efficacy data). Safety 
data will be summarised using the Safety analysis set, so study day is derived in relation to the 
date of first treatment (study day 1 for safety data).
3.1.2
Visit Windows
For summaries of vital signs, laboratory data, ECGs, Echo scans and ophthalmological 
examination, assessments will be assigned to calculated visit windows (using study day for 
safety data).   
The window for the visits following baseline will be constructed in such a way that the upper 
limit of the interval falls half way between the two visits.   


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If more than 1 assessment falls into a visit window, the value nearest the protocol defined 
assessment time point will be used for the summaries by visit, as this is most representative of 
the patients’ assessment at that time point. If two or more values fall within a time window 
and are equidistant to the protocol defined assessment time point, the value from the first time 
point will be used.  For summaries showing the maximum or minimum values on study, the 
maximum/minimum value recorded during the time period being summarised (e.g. 18 months 
or 3 years) will be used (regardless of where it falls in the interval).  Listings will display all 
values contributing to a time point for a patient; and also highlight the value for that patient 
that went into the table, wherever feasible.
See Section 3.2.3 for definition of visit windows for complete and clinical remission.
3.1.3
Handling of missing data
Safety assessment values of the form of “<x” (ie, below the lower limit of quantification 
(LLOQ)) or >x (i.e., above the upper limit of quantification (ULOQ)) will be imputed as “x” 
in the calculation of summary statistics but displayed as “<x”or “>x” in the listings.
For the sensitivity analyses using covariate (mutation status, histology status and age) adjusted 
logistic regression models, the following missing data approach for each covariate will be 
adopted:
!
Missing mutation status; add an additional ‘unknown’ category to make 3 
categories (positive, not detected, and unknown)
!
Missing histology status; add an additional ‘unknown’ category to make 4 
categories (papillary, follicular, poorly differentiated, and unknown)
!
Missing age; impute the mean of observed ages
3.2
Efficacy variables
3.2.1
Complete remission rate at 18 months post-RAI treatment
Complete remission rate is defined as the proportion of randomised patients who are alive and 
meet the following criteria at 18 months post-RAI treatment:
1.
Serum Tg levels < 1ng/mL during rhTSH stimulation, in the absence of interfering 
Tg antibodies, as assessed by standardised central laboratory analysis.  
2.
No confirmed evidence of thyroid cancera by neck ultrasound (US), as assessed by 
investigator site review.
3.
No confirmed radiological evidence of thyroid cancera, as assessed by blinded 
independent central review.  
4.
No histopathological evidence of thyroid cancer on FNA/biopsy when performed, 
as assessed by investigator site review.  


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5.
No further thyroid cancer therapy was administered in the first 18 months following 
the initial RAI treatment.
The complete remission rate will be calculated using all randomised patients (ITT population) 
as the denominator.
There are two main components to complete remission: biochemical remission and structural 
remission.  Biochemical remission is measured by Tg and structural remission is assessed by 
the imaging assessments US, MRI, CT and WBS in conjunction with biopsy/FNA.  
a Confirmation of evidence of structural DTC will be either histopathological (from a 
biopsy/FNA; as criterion 4 above), or RAI-avid disease. In this disease setting, structural 
abnormalities that are not RAI-avid and do not have confirmed histopathology consistent with 
DTC (ie are not biopsy proven) are considered benign in the absence of biochemical DTC.
I.e. Any abnormalities seen in US, CT or MRI unless confirmed by FNA/biopsy will be 
considered benign.
Staged approach to primary endpoint assessments
A staged approach will be taken for performing assessments contributing to the primary 
endpoint, to avoid unnecessary assessments for individual patients who received further 
therapy prior to the primary assessment, and for those patients not in biochemical remission 
(as determined by serum Tg levels in the absence of interfering Tg antibodies).
Full details of the staged approach to the primary endpoint assessments are outlined in the 
Clinical Study Protocol and Medical Imaging Independent Review Charter.  There will be 3 
stages of assessments.  Patients that have been re-treated for thyroid cancer will not have any 
further primary endpoint assessments performed, though they will be included in the ITT 
population (as not being in remission).  All patients who have not been re-treated for thyroid 
cancer will have stage 1 assessments performed.  The decision on whether to proceed to stage 
2 and 3 assessments for patients that have not been re-treated will be made at site, based on 
centrally analysed biochemical data (Tg and TgAb data).  Patients identified as not in 
biochemical remission will not be required to have all remaining imaging assessments.  For 
patients that have imaging assessments performed, the appropriate data will be sent to the 
imaging CRO for blinded independent central review to identify presence or absence of 
structural disease.
Derivation of primary endpoint of complete remission
The complete remission status of each patient will be determined programmatically by 
AstraZeneca or designee, by incorporating data on assessment dates, re-treatment provided by 
the site, biochemical data from the standardised central laboratory analysis, and structural 
disease assessment from the blinded, independent central review.  


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If a patient has received further therapy for thyroid cancer prior to the primary endpoint 
assessment, the patient will be classified as not in complete remission and no further data will 
be considered.
For patients that have not received further therapy for thyroid cancer, all imaging data will be 
sent to the imaging CRO. Determination of presence or absence of structural thyroid cancer 
will be made by the imaging CRO only for biochemically negative patients. A list of 
biochemically negative patients (based on standardised central laboratory analysis) will be 
provided by AstraZeneca to the imaging CRO to enable them to identify which patients to 
assess. 
The imaging CRO will assess the WBS, MRI and CT and also review the site assessment of 
neck US and biopsy findings for US, CT and MRI (if performed) to provide an overall 
assessment: presence or absence of structural thyroid cancer, or not evaluable based on all of 
the available information.  For the derivation of the complete remission endpoint, patients that 
are not evaluable for structural disease assessment will be considered as not achieving 
complete remission, regardless of the result of other assessments.    
AstraZeneca or designee will programmatically combine information on assessment dates, 
further therapy, biochemical data, and the determination of structural disease from the central 
imaging CRO, to determine the complete remission status of each patient as shown in Table 1.
A separate document to describe the algorithmic steps to determine the complete remission 
status of each patient based on Table 1 and CSP will be provided by AZ to the designee.
Table 1
Programmatic derivation of complete remission status
Further 
thyroid cancer 
therapya       
(re-treatment)
Biochemical datab
Structural 
disease 
assessmentc
Complete 
remission
Stimulated Tg
TgAb
Yes
Any 
Any
Any
No
No
< 1 ng/mL
Negatived
Absence of disease
Yes
No
≥ 1ng/mL
Any
Any
No
No
Any
Positived
Any
No
No
Any
Any
Presence of 
disease
No
No
NE
Any
Any
No
No
Any
NE
Any
No
No
Any
Any
NE
No
a As assessed by investigator at site 


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b As assessed by standardised central laboratory analysis
c As assessed by blinded, independent central review
d  If the stage 1 and stage 2 blood samples are discordant for TgAb status, then a third blood sample 10 days later 
(± 3days) is required. Only if the third sample is negative for TgAb will the overall result be considered negative.  
N/A primary endpoint assessments are not required for patients that have received further treatment for thyroid 
cancer in the previous 18 months.
NE Not evaluable (for example due to missing samples or assessments)
3.2.2
Clinical remission rate at 18 months post-RAI treatment
Clinical remission rate is defined as the proportion of randomised patients who are alive and 
meet the following criteria at 18 months post-RAI treatment: 
1.
Serum Tg levels < 1ng/mL during rhTSH stimulation, in the absence of interfering 
Tg antibodies, as assessed by standardised central laboratory analysis.
2.
No confirmed evidence of thyroid cancer by neck US, as assessed by investigator 
site review.
3.
No evidence of thyroid cancer by diagnostic WBS, as assessed by blinded 
independent central review.
4.
No histopathological evidence of thyroid cancer on FNA/biopsy when performed to 
clarify equivocal US findings, as assessed by investigator site review.  
5.
No further thyroid cancer therapy was administered in the first 18 months following 
the initial RAI treatment.
The clinical remission rate will be calculated using all randomised patients (ITT population) 
as the denominator.
Derivation of clinical remission status
The clinical remission status of each patient will be determined programmatically by 
AstraZeneca or designee, by incorporating data on re-treatment provided by the site, 
biochemical data from the standardised central laboratory analysis, structural disease 
assessment based on US by investigator site review and structural disease assessment based on 
WBS from the blinded, independent central review.  
If a patient has received further therapy for thyroid cancer prior to the primary endpoint 
assessment, the patient will be classified as not in clinical remission and no further data will 
be considered.
For patients that have not received further therapy for thyroid cancer:
!
A determination of presence or absence of structural thyroid cancer or not evaluable 
will be made by the investigator based on US and biopsy.  


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!
A determination of presence or absence of structural thyroid cancer or not evaluable 
will be made by the investigator based on WBS for only biochemically negative 
patients.  A list of biochemically negative patients (based on standardised central 
laboratory analysis) will be provided by AstraZeneca to the imaging CRO to enable 
them to identify which patients to assess.
AstraZeneca or designee will programmatically combine information on further therapy, 
biochemical data, determination of structural disease from the investigator site assessment of 
US and determination of structural disease from the central imaging CRO of WBS, to 
determine the clinical remission status of each patient as shown in Table 2.
A separate document to describe the algorithmic steps to determine the clinical remission 
status of each patient based on  Table 2 and CSP will be provided by AZ to the designee. 
Table 2
Programmatic derivation of clinical remission status
Further 
thyroid 
cancer 
therapya      
Biochemical data
Structural disease assessment
Clinical 
remission
Stimulated Tgb
TgAbb
US/biopsya
WBSc
Yes
Any
Any 
Any
Any 
No
No
<1 ng/mL
Negatived
Negative
Absence of 
disease
Yes
No
<1 ng/mL
Negatived
NE
Absence of 
disease
Yes
No
∀1 ng/mL
Any
Any
Any
No
No
Any
Positived
Any 
Any
No
No
Any
Any
Positive
Any
No
No
Any
Any
Any
Presence of 
disease
No
No
NE
Any
Any
Any
No
No
Any
NE
Any
Any
No
No
Any
Any
Any
NE
No
a As assessed by investigator at site 
b As assessed by standardised central laboratory analysis
c As assessed by blinded, independent central review
d  If the stage 1 and stage 2 blood samples are discordant for TgAb status, then a third blood sample 10 days later 
(± 3days) is required. Only if the third sample is negative for TgAb will the overall TgAb result be considered 
negative.  
N/A primary endpoint assessments are not required for patients that have received further treatment for thyroid 
cancer in the previous 18 months.
NE Not evaluable (for example due to missing samples or assessments)


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3.2.3
Visit windows for complete and clinical remission assessment
A staged approach will be taken for performing assessments contributing to the primary 
endpoint, to avoid unnecessary assessments for individual patients who received further 
therapy prior to the primary assessment and for those patients not in biochemical remission, 
therefore the assessments that contribute to primary endpoint will be performed on different 
dates.  These assessments are stimulated Tg (and TgAb using the same blood draw), US scan, 
MRI scan, CT scan and WBS.
The derivation of the primary endpoint is based on data on further therapy, biochemical data 
and a single overall assessment of structural disease from all of the available imaging 
modalities of local US results plus MRI, CT and WBS from the blinded, independent central 
review, as shown in Table 1.  However, the dates on which these components were performed 
will be incorporated into the derivation of the primary endpoint to ensure patients are assessed 
at least 18 months post-RAI treatment as follows.   
Any patient that has been re-treated for thyroid cancer prior to scheduled assessment at 18 
months post-RAI treatment (i.e. prior to 525 days) will be considered not to be in complete 
remission.
The date of the first assessment that contributes to the complete remission definition, i.e., the 
date that the stimulated Tg was performed, must be at least 75 weeks (525 days) post-RAI 
treatment. However, if a patient has any part of the composite endpoint assessment for Stage 1 
(suppressed Tg, TgAb, US and/or FNA/Biopsy) evaluated before 75 weeks (i.e. prior to 525 
days) post RAI-treatment and the remaining composite endpoint assessments for Stage 2 
(stimulated Tg, WBS) and Stage 3 (CT and MRI) evaluated at least 75 weeks (525 days) post 
RAI-treatment, then the patient will be considered in the derivation of biochemical, clinical 
and complete remission. In addition, there is no restriction on the date that the last 
assessment/scan that contributes to the complete remission definition must be performed.
If a patient has at least one part of the composite endpoint for Stage 2 or Stage 3 assessed 
before 75 weeks post-RAI treatment, and not repeated after this time point, or fails to 
complete the full set of primary endpoint assessments, then the patient will be considered not
to be in complete remission, regardless of the assessment of disease status.
3.3
Safety variables
3.3.1
Adverse events (AE)
The Medical Dictionary for Regulatory Activities (MedDRA) dictionary will be used to code 
the AEs.  AEs will be graded according to the National Cancer Institute Common 
Terminology Criteria for AEs (CTCAE) Version 4.   The CTCAE grade will be assigned by 
the investigator.


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During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as serious adverse events (SAEs) or discontinuation of 
investigational product due to adverse event (DAEs).   Based on the expert’s judgement, 
significant adverse events of particular clinical importance may, after consultation with the 
Global Patient Safety Physician, be considered other adverse events (OAEs) and reported as 
such in the Clinical Study Report.  A similar review of laboratory/vital signs/ECG data will 
be performed for identification of OAEs.
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction 
or significant additional treatment.
The denominator for AE summaries will be the Safety population.
3.3.2
Vital signs, laboratory data, ECGs, ECHO/MUGA, physical examination and 
ophthalmologic examination
Change from baseline in vital signs, laboratory data, ECGs, ECHO/MUGA, physical 
examination and ophthalmologic examination variables will be calculated for each post-dose 
visit during follow-up where this data was collected.  The baseline value will be the latest 
result obtained prior to the start of study treatment.
For laboratory data, CTCAE grade will be calculated at each visit.  The denominator used in 
laboratory summaries will only include evaluable patients, in other words those who had 
sufficient data to have the possibility of an abnormality.  For example: 
!
If a CTCAE criterion involves a change from baseline, evaluable patients would 
have both a pre-dose and at least 1 post-dose value recorded
!
If a CTCAE criterion does not consider changes from baseline, to be evaluable the 
patient need only have 1 post dose-value recorded
The denominator in vital signs, ECGs, ECHO/MUGA, physical examination and 
ophthalmologic examination data will include only patients in the Safety population with 
recorded data.
For ECG data, the Investigator’s assessment of the ECG (normal, borderline or abnormal) and 
heart rate, QRS, PR and QT will be recorded at each time-point.  QTcF (Fredericia) will be 
calculated programmatically by AstraZeneca or designee using the reported ECG values (RR 
and QT).
QTcF = QT / RR^ (1/3) where RR is in seconds
3.4
PK data
The plasma concentration-time data for selumetinib and N-desmethyl selumetinib will be 
analysed using non-linear mixed effects modelling.  The primary aims of that modelling will 


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be to characterise the pharmacokinetics of selumetinib and N-desmethyl selumetinib in the 
population studied, generate population and individual patient estimates of pharmacokinetic 
parameters, quantify the variability in those parameters and investigate covariates which may 
explain that variability.  In addition, if the data are suitable, potential relationships between 
plasma selumetinib/N-desmethyl selumetinib concentrations and efficacy and safety endpoints 
will be investigated using a graphical approach and/or appropriate PK/PD modelling 
techniques.  A detailed pharmacokinetic analysis plan will be written prior to database lock.  
The results of the analysis will be reported separately from the clinical study report (CSR).
3.5
Other data
3.5.1
Thyroid cancer recurrence
The occurrence and date of any thyroid cancer recurrence will be recorded for patients who 
have previously entered remission, either complete or clinical (at any point during the study or 
follow up periods).  The rate of thyroid cancer recurrence will be calculated using only 
patients who have achieved remission as the denominator.  
3.5.2
Survival status
The survival status and survival assessment date of all patients will be recorded.  Survival 
time will be calculated as the time from the date of randomisation to the date of death.  
Patients who have not died at the time of the final study follow up will be censored at the last 
date the patient was known to be alive.
3.5.3
Further therapy
The dates and type of any further therapy for thyroid cancer will be recorded during the study 
and follow up periods.
4.
ANALYSIS METHODS
4.1
General principles
Statistical analyses will be performed by, or under the guidance of, Biometrics and 
Information Sciences, AstraZeneca using SAS version 9.1.3 or later and, where appropriate, 
additional validated software.   These analyses will be performed in accordance with this 
Statistical Analysis Plan (SAP), which will detail analyses to be performed and summaries to 
be produced for the CSR.
The database will be cleaned, locked and released for analysis after all patients have 
completed their 18 month assessments. A CSR will be developed for this analysis, including 
the result of the primary endpoint analysis. An updated CSR will be released upon completion 
of analyses after all patients have completed the study (3 years of follow-up), however the 
primary analysis will not be repeated at this point. Table 3 details the time points of analysis 
for each endpoint.


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4.2
Analysis methods
Since there is only one primary endpoint/comparison of interest (complete remission rate at 18 
months for selumetinib vs. placebo in the ITT population), the primary endpoint will be 
considered statistically significant if the two-sided p-value is less than 0.05. 
A summary of the endpoints to be analysed and analyses to be performed is shown in Table 3.
Table 3
Statistical analyses and pre-planned sensitivity analyses
Endpoint
Analysis 
Population
Analyses
Analysis at:
18
months
3
years
Complete 
Remission Rate
ITT
Primary analysis:
Logistic regression with treatment as 
the only covariate.


Sensitivity analyses:
Logistic regression adjusted for 
mutation status, histology status and 
age

Logistic regression with treatment as 
the only covariate, using the treatment 
compliant population.

Logistic regression with treatment as 
the only covariate using protocol 
defined 8 week window

Logistic regression with treatment as 
the only covariate ignoring any 
window

Logistic regression with treatment as 
the only covariate, excluding patients 
with high TSH.

Other analyses:
By treatment descriptive summaries
Subgroup analyses (see Section 4.2.4)


BRAF/NRAS
mutation positive
Secondary analysis:
Logistic regression with treatment as 
the only covariate.

Sensitivity analysis:
Logistic regression adjusted for 
histology status and age



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Table 3
Statistical analyses and pre-planned sensitivity analyses
Endpoint
Analysis 
Population
Analyses
Analysis at:
18
months
3
years
Other analyses:
By treatment descriptive summaries
Subgroup analyses (see Section 4.2.4)


Clinical 
Remission Rate
ITT
Secondary analysis:
Logistic regression with treatment as 
the only covariate.

Sensitivity analysis:
Logistic regression adjusted for 
mutation status, histology status and 
age

Other analyses:
By treatment descriptive summaries
Subgroup analyses (see Section 4.2.4)


BRAF/NRAS
mutation positive
Secondary analysis:
Logistic regression with treatment as 
the only covariate.

Sensitivity analysis:
Logistic regression adjusted for 
histology status and age

Other analyses:
By treatment descriptive summaries
Subgroup analyses (see Section 4.2.4)


Thyroid cancer 
recurrence
ITT
By treatment descriptive summaries
Kaplan-Meier plot if sufficient data


Overall survival
ITT
By treatment descriptive summaries
Kaplan-Meier plot if sufficient data


Use of further 
thyroid cancer 
therapy
ITT
By treatment descriptive summaries


Adverse events
Safety
By treatment descriptive summaries of 
any AEs occurring between treatment 
start and 30 days after last treatment 
dose.



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Table 3
Statistical analyses and pre-planned sensitivity analyses
Endpoint
Analysis 
Population
Analyses
Analysis at:
18
months
3
years
By treatment descriptive summaries of 
any treatment-related AEs occurring 
between 30 days after last treatment 
dose and end of follow-up.

By treatment descriptive summaries of
any serious AEs occurring between 
treatment start and end of follow-up.

Vital signs
Safety
By treatment descriptive summaries

Laboratory data
Safety
By treatment descriptive summaries


ECGs
Safety
By treatment descriptive summaries

ECHO/MUGA
Safety
By treatment descriptive summaries

Physical 
examination
Safety
By treatment descriptive summaries

Ophthalmologic 
examination
Safety
By treatment descriptive summaries

PK
PK
Population PK analyses (to be 
described in a separate PK analysis 
plan).

4.2.1
Primary analysis
The primary analysis will be an analysis of complete remission rate at 18 months and will 
compare selumetinib in combination with RAI vs. placebo in combination with RAI in the 
ITT population using a logistic regression model including treatment as the only covariate. 
Results will be presented in terms of the odds ratio together with its associated 95% profile 
likelihood CI and two-sided p-value based on profile likelihood. 
A summary table will also be produced showing the number of patients that are in complete 
remission, not in complete remission due to re-treatment for thyroid cancer prior to scheduled 
assessment at 18 months post-RAI treatment or due to missing assessments (i.e. local lab, 


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wrong lab kit, no stage 2 or 3, missed visit, withdraw consent etc.). In addition, a listing of 
assessments/scans that contribute to the complete remission definition were performed will be 
presented.
4.2.2
Secondary analyses
Secondary analyses will be performed using a logistic regression model including treatment as 
the only covariate for the following endpoints and populations.
!
Complete remission rate at 18 months post RAI treatment (BRAF/NRAS positive 
population)
!
Clinical remission rate at 18 months post RAI treatment (ITT population)
!
Clinical remission rate at 18 months post RAI treatment (ITT and BRAF/NRAS 
positive population)
Results will be presented in terms of the odds ratio, together with its associated 95% profile 
likelihood CI and two-sided p-value based on profile likelihood.
4.2.3
Sensitivity analyses
4.2.3.1
Logistic regression model including treatment and adjusted for covariates
A sensitivity analysis for each of the primary and secondary analyses will be performed using 
a logistic regression model including treatment and adjusted for the covariates mutation status 
(ITT population only), histology status, and age, provided there are enough data points for a 
meaningful analysis. If the model fails to converge, levels of the problematic covariate may be 
collapsed or if necessary excluded from the model. Specifically, this sensitivity analysis will 
be performed for each of the following:
!
Complete remission rate at 18 months post RAI treatment (ITT population)
!
Complete remission rate at 18 months post RAI treatment (BRAF/NRAS positive 
population)
!
Clinical remission rate at 18 months post RAI treatment (ITT population)
!
Clinical remission rate at 18 months post RAI treatment (BRAF/NRAS positive 
population)
The logistic regression model will be fitted with the following effects (where specified) 
regardless of whether the inclusion of the effects significantly improves the fit of the model. 
PROC LOGISTIC (SAS®) will be used for the statistical analysis.  The variables shown in 
Table 4 will be used.


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Table 4
Data specification for variables in logistic regression models and/or 
subgroup analyses
Variable
Variable Type
Variable Specification
Complete or 
Clinical 
Remissiona
Dichotomous outcome
1=Yes
0=No
Treatmentb
Unordered categorical 
covariate
1=selumetinib + RAI
0=placebo + RAI
BRAF/NRAS
mutation statusc
Unordered categorical 
covariate
A= BRAF mutation positive or NRAS mutation 
positive
B= BRAF mutation not detected and NRAS
mutation not detected
C=unknown
BRAF mutation 
statusd
Unordered categorical 
covariate
A= BRAF mutation positive
B= BRAF mutation not detected 
C=unknown
NRAS mutation 
statusd
Unordered categorical 
covariate
A= NRAS mutation positive
B= NRAS mutation not detected
C=unknown
Histology status
Unordered categorical 
covariate
A=papillary
B=follicular
C=poorly differentiated
D=unknown
Age
Continuous covariate
Number in years
Gendere
Unordered categorical 
covariate
A=female
B=male
Racee
Unordered categorical 
covariate
A=Caucasian
B=Oriental
C=other
a For definitions of complete and clinical remission refer to Sections 3.2.1 and 3.2.2 respectively. PROC 
LOGISTIC will use the DESCENDING option in order to model the probability of remission = 1 (yes).
b The PARAM=REF option on the CLASS statement will be used, so that parameter effects of class main effects 
using the reference coding scheme estimate the difference in the effect of each non-reference level 
compared to the effect of the reference level.  The REF = first/last option will be used so that the 
placebo+RAI treatment group is the reference group.  Parameter effects will not be presented in the results
c BRAF/NRAS mutation status variable will be included as covariates in the sensitivity and subgroup analyses on 
ITT population only
d The separate BRAF and NRAS mutation status variables will be included as covariates in the subgroup analyses 
on ITT population only, see Section 4.2.4


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e Gender, race will be included as covariates in the subgroup analyses only, see Section 4.2.4
The results of all the logistic regression analyses will be presented in terms of an odds ratio for 
the treatment effect together with its associated 95% profile likelihood confidence interval and 
2-sided p-value.  The p-value will be based on twice the change in log-likelihood resulting 
from the addition of a treatment factor to a model that contains the covariates defined above.
If there are any imbalances in the covariates defined above, adjusted response rates whose 
odds ratio exactly matches the odds ratio from the primary analyses (weighted in line with the 
prevalence of covariates) will be presented.
4.2.3.2
Additional sensitivity analyses
The primary endpoint analysis, a logistic regression model including treatment as the only 
covariate for complete remission at 18 months, will be repeated separately for the following:
!
using the treatment-compliant population.
!
classifying patients that had their first assessment started at 18 months ± 2 weeks 
[534 – 562 days] following the patient’s RAI dose, and all necessary primary 
endpoint assessments were completed within a 8 week period to be in complete 
remission. 
!
to allow patients that were identified as being in complete remission outside of the 
specified time windows to be classed as being in complete remission, in order to
investigate time bias between arms.
!
excluding patients with high TSH. Elevated TSH can be caused by poor compliance 
and can mean a patient is less likely to achieve remission, therefore this sensitivity 
analysis excludes patients with high TSH, which is defined as a value >10 mIU/L 
recorded, at any point from the start of treatment, by standardised central laboratory 
analysis.
4.2.4
Subgroup Treatment Effects
The complete and clinical remission rates at month 18 will be presented for each treatment 
arm, overall and by each covariate subgroup separately, for the ITT and BRAF/NRAS 
mutation positive population.  
The extent to which the treatment effect is consistent across the subgroups mutation status 
(ITT population only), histology status, age, gender, and race will be assessed for the ITT 
population and in the BRAF/NRAS mutation positive population.  
The presence of a quantitative interaction will be assessed by means of an overall global 
interaction test.  This will be performed by comparing the fit (likelihood ratio test) of a model 
including all covariate-by-randomised treatment interaction terms, treatment and covariate 


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terms with a model that excludes the interaction terms.  If the global interaction test is found 
to be statistically significant at the 10% significance level, an attempt to determine the cause 
and type of interaction will be made.  Stepwise backward selection will be performed on the 
saturated model, whereby (using a 10% level throughout) the least significant interaction 
terms are removed one-by-one and any newly significant interactions re-included until a final 
model is reached where all included interactions are significant and all excluded interactions 
are non-significant.   Throughout this process all main effects will be included in the model 
regardless of whether the corresponding interaction term is still present.   This approach will 
identify the factors that independently alter the treatment effect and prevent identification of 
multiple correlated interactions.   
For quantitative interactions identified, the presence of any qualitative interactions will be 
assessed using the approach of Gail and Simon (Gail & Simon 1985).  For categorical 
covariates the test statistics, based on the appropriate degrees-of-freedom, can be taken 
directly from the paper.  For the continuous covariate, the approach will be adapted as 
follows:
!
Identify the cut-point (-#1/#3) of the covariate where the odds ratio for the treatment 
effect is 1, where #1 is the treatment parameter estimate and #3 is the treatment-by-
covariate parameter estimate.
!
Re-analyse the data separately for the values of the covariate above and below the 
cut-point and use the separate chi-square values in the Simon and Gail test.
Subgroup data (BRAF or NRAS mutation status, BRAF mutation status, NRAS mutation 
status (ITT population only), histology status, age, gender, and race) will be summarised by a 
forest plot where the odds ratio is plotted on the log scale.  For this, age will be categorised as 
≤45 and >45 years.  The treatment effect and 95% confidence intervals for each level of the 
subgroup will be obtained from a single logistic regression model that contains a treatment, 
factor and treatment-by-factor interaction term.
To assess the impact of known versus unknown covariate information separate logistic 
regression models will be performed containing treatment, factor and treatment-by-factor 
interaction term, for the following factors, if sufficient data, e.g., minimum 10 patients per 
treatment-by-factor level, to be meaningful to do so:
!
BRAF or NRAS mutation status (known and unknown)
!
BRAF mutation status (known and unknown)
!
NRAS mutation status (known and unknown)
!
Histology status (known and unknown)
The treatment effect and 95% confidence intervals for each level of the known subgroup will 
presented alongside the other categories in the appropriate forest plots; i.e. for each mutation 


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status there will be treatment odds ratios and 95% confidence intervals for positive, not 
detected, known (combined positive and not detected group) and unknown, and for histology 
status there will be treatment odds ratios and 95% confidence intervals for papillary, follicular, 
poorly differentiated, known (combined papillary, follicular, and poorly differentiated group) 
and unknown.
4.2.5
Demographic and baseline characteristics
The following baseline characteristics will be listed for each patient and summarised for all 
patients in the ITT analysis set by treatment group:
!
Patient disposition
!
Inclusion in analysis populations
!
Important protocol deviations
!
Demography (age (at informed consent), sex, race and thnic group)
!
Patient characteristics including height and weight
!
Patient recruitment by country and centre
!
Past and current medical history
!
Relevant surgical history
!
Disease characteristics at baseline
!
Primary tumor and TNM classification at original diagnosis
!
Allowed and disallowed concomitant medications (presented by ATC classification 
system) for all patients in the safety analysis set
4.2.6
Safety
Safety data will not be formally analysed.  The safety analysis set will be used for the 
reporting of safety data.
4.2.6.1
Adverse events
AE data will be listed for each patient and summarised by treatment received according to 
System Organ Class (SOC) and preferred term.  
For patients who have a dose modification, all AEs (due to drug or otherwise) will be assigned 
to the initial treatment arm.  
AE summaries will include all of the following:


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!
Any AEs  occurring after commencement of study treatment and within 30 days of 
the last dose of study medication,
!
Selumetinib or RAI related AEs occurring between 30 days after the last dose of 
study medication and the final study visit at 3 years following the initial RAI dose.
!
All SAEs occurring after commencement of study treatment until the final study 
visit at 3 years following the initial RAI dose.
AEs occurring before commencement of study treatment will not be included in AE 
summaries but will be included and identified in the patient listings.
Any AE with a missing onset date will be considered an on treatment AE unless the stop date 
of the AE indicates otherwise.   Similarly, any AE with a partial onset date will be considered 
an on treatment AE unless the partial onset date or the stop date indicates otherwise.
4.2.6.2
Vital signs, laboratory data, ECGs, ECHO/MUGA, physical examination and 
ophthalmologic examination
No formal analyses of vital signs, laboratory data, ECGs, ECHO/MUGA, physical 
examination and ophthalmologic examination data will be performed; this data will be 
summarised and listed.  
4.2.7
Other analyses
4.2.7.1
Thyroid cancer recurrence
Very few thyroid cancer recurrences are expected on this study, therefore no formal analysis 
of thyroid cancer recurrence data will be performed; data will be listed and summarised by 
treatment arm for all patients in the ITT analysis set.  Kaplan-Meier plots of time to recurrence 
(defined as a patient whose thyroid cancer has subsequently recurred, or the patient has a new 
malignancy) may be produced if appropriate, for those patients classed as being in complete 
remission at 18 months (or later).
4.2.7.2
Survival status
Very few deaths are expected on this study therefore no formal analysis of survival data will 
be performed; data will be listed by individual patients and summarised by treatment arm for 
all patients in the ITT analysis set.  Kaplan-Meier plots of survival may be produced if 
appropriate.
4.2.7.3
Further therapy
No formal analysis of further therapy data will be performed; data will be listed and 
summarised by treatment arm for all patients in the ITT analysis set.  Kaplan-Meier plots of 
time to further therapy may be produced if appropriate.


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4.2.7.4
PK
Plasma selumetinib, N-desmethyl selumetinib plasma concentrations will be listed for each 
patient. A population PK analysis will be carried out. The results of this analysis will be 
reported outside of the CSR. 
4.2.7.5
Genetics
Any genetic data analysis (other than BRAF and NRAS) will be planned outside this SAP and 
reported outside the CSR for this study.
4.2.7.6
Biomarker data
BRAF and NRAS mutation assessment of tumour biopsy will be used to identify patients for 
this primary patient population. The results of any other exploratory biomarker investigations 
will be planned outside this SAP and reported outside the CSR for this study.
5.
INTERIM ANALYSES – NOT APPLICABLE
6.
CHANGES OF ANALYSIS FROM PROTOCOL 
In the protocol section 6.4.5 (Derivation of primary endpoint of complete remission) it is 
stated:
“The first assessment must be started at 18 months ± 2 weeks following the patient’s RAI 
dose, and all necessary primary endpoint assessments must be completed within a 8 week 
period. If a patient has assessments/scans that fall outside of these time windows, the patient 
will be considered not to be in complete remission, regardless of the assessment of disease 
status.”
Change of analysis:
Patients who did not complete a full set of assessments within 8 weeks of commencing the 18 
month primary endpoint assessments but who do have a full set of assessments at or following 
the time the 18 month assessment window began, will be considered for the primary endpoint. 
Specifically, patients whose any part of the composite endpoint assessment for Stage 1 
(suppressed Tg, TgAb, US and/or FNA/Biopsy) was evaluated before 75 weeks (i.e. prior to 
525 days) provided that all the composite endpoint assessments for Stage 2 (stimulated Tg, 
WBS) and Stage 3 (CT and MRI) were evaluated at least 75 weeks (≥525 days) post RAI-
treatment will be considered for the primary endpoint.  
The same time window derivations will be applied to the secondary analysis of clinical 
remission.


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In addition the sensitivity analyses (SAP 4.2.3.2) were clarified in light of the change to 
programmatic derivation of the primary and secondary analyses.
Rationale:
During the study it became clear that some patients found it difficult to attend the site for all 
stages of the assessment in the study mandated time windows due to numerous reasons (e.g. 
work or personal commitments, difficulties scheduling with several different departments, 
equipment failure at the site requiring rescheduling, etc.). If the assessment shows that the 
patient has not relapsed at a time point beyond 18 months, then it is expected the patient 
would not have relapsed at the earlier 18 month time point. In an attempt to include as 
comprehensive an assessment for Complete Remission, the 8 week window to complete all 
assessment stages has been removed from the programming derivation (but not from the 
guidance given to sites).
It is considered that a patient who has not required retreatment and is in complete remission 
(e.g. no evidence of relapse) later than 18 months can be assumed to have been in complete 
remission at the 18 month timepoint. As such, in the programming definition, the upper 
window around 18 months has been removed.
‘At least 75 weeks’ will be used in the programming criteria for the start of the 18 month 
assessment window. This allows a slightly larger window than the guidance given in the CSP 
to the investigator (18 months +/- 2 weeks). This is because the calculation of 18 months may 
vary slightly depending whether the site using calendar months or 365.25 days x 1.5 to choose 
the 18 month visit date (and the specific definition of 18 months is not given in the CSP). The 
‘At least 75 weeks’ criterion has also been extended to allow inclusion in the derivation of 
biochemical, clinical and complete remission of patients whose any part of  the composite 
endpoint assessment for Stage 1 (suppressed Tg, TgAb, US and/or FNA/Biopsy) evaluated 
before 75 weeks (i.e. prior to 525 days) provided that all the composite endpoint assessments 
for Stage 2 (stimulated Tg, WBS) and Stage 3 (CT and MRI) were evaluated at least 75 weeks 
(≥525 days) post RAI-treatment. Rationale is that the Stage 2 and 3 are the main drivers to 
assess biochemical and structural remission provided though all assessments have been 
implemented.
7.
REFERENCES
Gail & Simon 1985
Gail M & Simon R.  Testing for qualitative interactions between treatment effects and subject 
subsets.  Biometrics 1985; 41:361-72.


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