Trial Outcomes & Findings for ZD6474 (ZACTIMA™) Phase III Study in EGFR Failures (NCT NCT00404924)

Last Updated: 2016-09-30

Results Overview

Overall Survival (OS) is defined as the time from date of randomization until death. Any blinded/unknown patient which have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive (ie, their status must be known at the censored date and should not be lost to follow up or unknown).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1140 participants

Primary outcome timeframe

Time to death in months

Results posted on

2016-09-30

Participant Flow

First patient enrolled 08 November 2006, last patient enrolled 09 October 2008, cut off date 19 October 2009. 1168 patients were enrolled in the study.

Participant milestones

Participant milestones
Measure	Vandetanib 300 mg vandetanib (300 mg daily) plus best supportive care	Placebo Placebo plus best supportive care
Overall Study STARTED	617	307
Overall Study COMPLETED	14	1
Overall Study NOT COMPLETED	603	306

Reasons for withdrawal

Reasons for withdrawal
Measure	Vandetanib 300 mg vandetanib (300 mg daily) plus best supportive care	Placebo Placebo plus best supportive care
Overall Study Adverse Event	75	16
Overall Study Condition under investigation worsened	475	264
Overall Study Lost to Follow-up	1	1
Overall Study Withdrawal by Subject	26	13
Overall Study Other	25	11
Overall Study Randomised but not received treatment	1	1

Baseline Characteristics

ZD6474 (ZACTIMA™) Phase III Study in EGFR Failures

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Vandetanib 300 mg n=617 Participants vandetanib (300 mg daily) plus best supportive care	Placebo n=307 Participants Placebo plus best supportive care	Total n=924 Participants Total of all reporting groups
Age, Continuous	59.8 years n=5 Participants	60.6 years n=7 Participants	60 years n=5 Participants
Sex: Female, Male Female	329 Participants n=5 Participants	160 Participants n=7 Participants	489 Participants n=5 Participants
Sex: Female, Male Male	288 Participants n=5 Participants	147 Participants n=7 Participants	435 Participants n=5 Participants

PRIMARY outcome

Timeframe: Time to death in months

Outcome measures

Outcome measures
Measure	Vandetanib 300 mg n=617 Participants vandetanib (300 mg daily) plus best supportive care	Placebo n=307 Participants Placebo plus best supportive care
Overall Survival (OS)	8.5 Months Interval 7.81 to 9.76	7.8 Months Interval 6.08 to 9.17

SECONDARY outcome

Timeframe: RECIST tumour assessments carried out every 8 weeks from randomisation until objective disease progression

Median time (in months) from randomisation until objective disease progression (determined by RECIST assessments) or death (by any cause in the absence of objective progression) provided death is within 3 months from the last evaluable RECIST assessment

Outcome measures

Outcome measures
Measure	Vandetanib 300 mg n=617 Participants vandetanib (300 mg daily) plus best supportive care	Placebo n=307 Participants Placebo plus best supportive care
Progression-Free Survival (PFS)	1.9 month Interval 1.84 to 2.23	1.8 month Interval 1.74 to 1.84

SECONDARY outcome

Timeframe: Each patient was assessed for objective response from the sequence of RECIST scan data up to data cut off. RECIST tumour assessments carried out every 8 weeks from randomisation until objective disease progression.

The ORR is the number of patients that are responders ie those patients with a confirmed best objective response of complete response (CR) or partial response (PR) as defined by RECIST criteria. The categories for best objective response are CR, PR, stable disease (SD)\>= 8 weeks, progressive disease (PD) or NE.

Outcome measures

Outcome measures
Measure	Vandetanib 300 mg n=617 Participants vandetanib (300 mg daily) plus best supportive care	Placebo n=307 Participants Placebo plus best supportive care
Objective Response Rate (ORR)	16 Participants	2 Participants

SECONDARY outcome

Timeframe: RECIST tumour assessments carried out every 8 weeks from randomisation until objective disease progression

Disease control rate is defined as the number of patients who achieved disease control at 8 weeks following randomisation. Disease control at 8 weeks is defined as a best objective response of complete response (CR), partial response (PR) or stable disease (SD) \>= 8 weeks

Outcome measures

Outcome measures
Measure	Vandetanib 300 mg n=617 Participants vandetanib (300 mg daily) plus best supportive care	Placebo n=307 Participants Placebo plus best supportive care
Disease Control Rate (DCR)	189 Participants	48 Participants

SECONDARY outcome

Timeframe: RECIST tumour assessments carried out every 8 weeks from randomisation until objective disease progression

Response is defined as a confirmed best objective response of CR or PR. Duration of response is defined as time from the date of first documented response until date of documented progression or death in the absence of disease progression (provided death is within 3 months of last RECIST assessment)

Outcome measures

Outcome measures
Measure	Vandetanib 300 mg n=16 Participants vandetanib (300 mg daily) plus best supportive care	Placebo n=2 Participants Placebo plus best supportive care
Duration of Response (DoR)	23.9 Weeks Interval 16.57 to 27.0	24.3 Weeks Interval 16.0 to 32.57

SECONDARY outcome

Timeframe: Disease-related symptom assessments are to be administered at screening (within 7 days before the first dose of study medication) and every 4 weeks thereafter, at discontinuation of study treatment and at the 30-day follow-up visit

Time to deterioration in symptoms is defined as the interval from the date of randomization to the first assessment of 'worsened' with no visit assessment of 'improved' within the next 28 days. Where assessment is by a selection of questions from the Functional Assessment of Cancer Therapy for Lung Cancer (FACT-L) questionnaire.

Outcome measures

Outcome measures
Measure	Vandetanib 300 mg n=617 Participants vandetanib (300 mg daily) plus best supportive care	Placebo n=307 Participants Placebo plus best supportive care
Time to Deterioration of Disease-related Symptoms (TDS) by Questionnaire - the Lung Cancer Subscale (LCS) a Selection of the FACT-L Focusing on Symptoms of Lung Cancer Plus Pain and Fatigue (LCS-PF)	6.1 weeks Interval 5.14 to 8.14	7.1 weeks Interval 5.86 to 8.43

Adverse Events

Vandetanib

Serious events: 160 serious events

Other events: 557 other events

Deaths: 0 deaths

Placebo

Serious events: 63 serious events

Other events: 234 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Trial Transparency Team

Sanofi

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Vandetanib n=619 participants at risk Vandetanib 300 mg	Placebo n=303 participants at risk Placebo
Blood and lymphatic system disorders Febrile Neutropenia	0.48% 3/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.00% 0/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Blood and lymphatic system disorders Anaemia	0.00% 0/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.66% 2/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Blood and lymphatic system disorders Thrombocytopenia	0.32% 2/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.66% 2/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Blood and lymphatic system disorders Leukopenia	0.00% 0/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.33% 1/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Blood and lymphatic system disorders Neutropenia	0.16% 1/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.33% 1/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Cardiac disorders Atrial Fibrillation	0.32% 2/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.00% 0/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Cardiac disorders Cardiac Failure	0.32% 2/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.00% 0/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Cardiac disorders Myocardial Infarction	0.32% 2/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.33% 1/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Cardiac disorders Angina Pectoris	0.00% 0/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.33% 1/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Cardiac disorders Arrhythmia	0.16% 1/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.00% 0/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Cardiac disorders Cardiac Arrest	0.16% 1/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.00% 0/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Cardiac disorders Cardiac Valve Disease	0.16% 1/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.00% 0/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Cardiac disorders Pericardial Effusion	0.00% 0/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.33% 1/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Ear and labyrinth disorders Deafness	0.16% 1/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.00% 0/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Ear and labyrinth disorders Vertigo	0.00% 0/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.33% 1/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Endocrine disorders Hyperthyroidism	0.16% 1/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.00% 0/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Eye disorders Diplopia	0.16% 1/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.00% 0/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Eye disorders Vision Blurred	0.16% 1/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.00% 0/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Eye disorders Visual Acuity Reduced	0.16% 1/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.00% 0/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Diarrhoea	1.3% 8/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.00% 0/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Vomiting	0.65% 4/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.99% 3/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Nausea	0.32% 2/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.33% 1/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Abdominal Distension	0.16% 1/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.00% 0/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Abdominal Pain	0.16% 1/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.00% 0/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Ascites	0.00% 0/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.33% 1/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Constipation	0.16% 1/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.00% 0/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Duodenal Ulcer	0.16% 1/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.00% 0/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Enteritis	0.16% 1/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.00% 0/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Gastrointestinal Perforation	0.00% 0/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.33% 1/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Gastrooesophageal Reflux Disease	0.16% 1/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.00% 0/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Gingival Pain	0.16% 1/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.00% 0/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Ileus Paralytic	0.16% 1/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.00% 0/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Intestinal Haemorrhage	0.00% 0/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.33% 1/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Intestinal Perforation	0.00% 0/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.33% 1/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Neutropenic Colitis	0.16% 1/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.00% 0/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Pancreatitis	0.16% 1/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.00% 0/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Paraesthesia Oral	0.00% 0/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.33% 1/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Pneumatosis Intestinalis	0.16% 1/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.00% 0/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Proctalgia	0.16% 1/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.00% 0/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Subileus	0.00% 0/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.33% 1/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS

Other adverse events
Measure	Vandetanib n=619 participants at risk Vandetanib 300 mg	Placebo n=303 participants at risk Placebo
Blood and lymphatic system disorders Anaemia	3.1% 19/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	6.3% 19/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Diarrhoea	45.9% 284/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	11.2% 34/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Nausea	22.3% 138/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	16.8% 51/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Constipation	14.2% 88/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	20.8% 63/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Vomiting	13.2% 82/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	11.9% 36/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Stomatitis	5.5% 34/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	4.3% 13/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Gastrointestinal disorders Abdominal Pain	4.2% 26/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	6.3% 19/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
General disorders Fatigue	17.6% 109/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	16.5% 50/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
General disorders Asthenia	10.0% 62/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	9.9% 30/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
General disorders Pyrexia	7.1% 44/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	9.6% 29/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
General disorders Oedema Peripheral	5.3% 33/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	9.6% 29/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
General disorders Weight Decreased	7.6% 47/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	5.9% 18/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
General disorders Electrocardiogram Qt Prolonged	6.0% 37/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	0.33% 1/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Metabolism and nutrition disorders Decreased Appetite	23.1% 143/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	20.8% 63/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Musculoskeletal and connective tissue disorders Back Pain	8.7% 54/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	6.3% 19/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Musculoskeletal and connective tissue disorders Musculoskeletal Pain	3.6% 22/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	6.6% 20/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Nervous system disorders Dizziness	11.0% 68/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	8.9% 27/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Nervous system disorders Headache	9.9% 61/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	7.9% 24/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Psychiatric disorders Insomnia	10.2% 63/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	7.9% 24/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Renal and urinary disorders Proteinuria	9.0% 56/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	3.3% 10/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Respiratory, thoracic and mediastinal disorders Cough	17.4% 108/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	17.5% 53/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Respiratory, thoracic and mediastinal disorders Dyspnoea	15.8% 98/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	17.2% 52/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Skin and subcutaneous tissue disorders Rash	41.7% 258/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	10.9% 33/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Skin and subcutaneous tissue disorders Pruritus	11.3% 70/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	5.3% 16/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Skin and subcutaneous tissue disorders Dry Skin	7.9% 49/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	2.6% 8/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Vascular disorders Hypertension	25.8% 160/619 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS	3.0% 9/303 The Safety Analysis Set included 922 patients (619 vandetanib \& 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS