Comparing complete remission after treatment with selumetinib/placebo in patient with differentiated thyroid cancer - ASTRA

Study identifier:D1532C00065

ClinicalTrials.gov identifier:NCT01843062

EudraCT identifier:2013-000423-14

CTIS identifier:N/A

Terminated/Withdrawn

Official Title

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

Medical condition

Differentiated Thyroid Cancer

Phase

Phase 3

Healthy volunteers

Study drug

Selumetinib, Placebo, Radioactive Iodine Therapy

Sex

All

Actual Enrollment

233

Study type

Interventional

Age

18 Years - 130 Years

Date

Study Start Date: 27 Aug 2013

Primary Completion Date: 18 May 2018

Study Completion Date: 06 Mar 2019

Study design

Allocation: Randomized
Endpoint Classification: Safety
Intervention Model: Parallel Assignment
Masking: Double Blind
Primary Purpose: Treatment

Verification:

Verified 01 Aug 2019 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Location

Research Site

Rio de Janeiro, Brazil

Location

Research Site

Porto Alegre, Brazil

Location

Research Site

Ribeirão Preto, Brazil

Location

Research Site

São José do Rio Preto, Brazil

Location

Research Site

São Paulo, Brazil

Location

Research Site

Odense C, Denmark, 5000

Location

Research Site

ANGERS CEDEX 01, France, 49033

Location

Research Site

Bordeaux Cedex, France, 33076

Arms	Assigned Interventions
Experimental: Selumetinib Selumetinib plus Radioactive Iodine Therapy	Drug: Selumetinib 3 capsules of 25 mg strength orally twice a day for approximately 5 weeks treatment period Other Name: N/A Drug: Radioactive Iodine Therapy 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) Other Name: N/A
Placebo Comparator: Placebo Placebo plus Radioactive Iodine Therapy	Drug: Placebo 3 capsules ( to match Selumetinib capsules) orally twice a day for approximately 5 weeks treatment period Other Name: N/A Drug: Radioactive Iodine Therapy 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) Other Name: N/A

Arms

Assigned Interventions

Experimental: Selumetinib
Selumetinib plus Radioactive Iodine Therapy

Drug: Selumetinib
3 capsules of 25 mg strength orally twice a day for approximately 5 weeks treatment period

Other Name: N/A

Drug: Radioactive Iodine Therapy
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)

Other Name: N/A

Placebo Comparator: Placebo
Placebo plus Radioactive Iodine Therapy

Drug: Placebo
3 capsules ( to match Selumetinib capsules) orally twice a day for approximately 5 weeks treatment period

Other Name: N/A

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Study conducted between 27 Aug 2013 and 06 Mar 2019. 42 centres in 8 countries randomised patients in the study. A primary analysis was performed for the 18 months post-radioactive iodine (RAI) treatment period with a data cut-off of 18 May 2018. All primary and secondary outcome measures were reported at the time of the primary analysis.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Eligible patients with differentiated thyroid cancer at high risk of primary treatment failure were randomly assigned (ratio 2:1), to receive selumetinib in combination with adjuvant RAI therapy or placebo and adjuvant RAI therapy for a period of approximately 5 weeks.

Reporting Groups

	Description
Selumetinib 75 mg BD + RAI	Patients received selumetinib (75 milligrams [mg], orally twice daily [BD]), for a period of approximately 5 weeks. Selumetinib was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 millicuries (mCi). To stimulate iodide uptake, patients received a recombinant human thyroid stimulating hormone (rhTSH) injection for each of the 2 days immediately prior to RAI therapy.
Placebo + RAI	Patients received placebo capsules (to match selumetinib, orally BD), for a period of approximately 5 weeks. Placebo was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.

Description

Selumetinib 75 mg BD + RAI

Patients received selumetinib (75 milligrams [mg], orally twice daily [BD]), for a period of approximately 5 weeks. Selumetinib was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 millicuries (mCi). To stimulate iodide uptake, patients received a recombinant human thyroid stimulating hormone (rhTSH) injection for each of the 2 days immediately prior to RAI therapy.

Placebo + RAI

Patients received placebo capsules (to match selumetinib, orally BD), for a period of approximately 5 weeks. Placebo was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.

Participant Flow: Overall Study

	Selumetinib 75 mg BD + RAI	Placebo + RAI
STARTED	155	78
Intention to treat (ITT) analysis set	155	78
Safety analysis set	154	77
BRAF/NRAS mutation positive analysis set	91	51
Ongoing at primary analysis data cut-off	134	71
COMPLETED	133	69
NOT COMPLETED	22	9
Protocol Violation	1	0
New treatment following progression	2	0
Pregnancy	1	0
Adverse Event	2	0
Incorrect randomisation	1	0
Withdrawal by Subject	12	3
Death	1	2
Lost to Follow-up	2	4

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

The ITT analysis set included all randomised patients. Patients who were randomised but did not subsequently go on to receive selumetinib/placebo were included in the ITT analysis set.

Reporting Groups

	Description
Selumetinib 75 mg BD + RAI	Patients received selumetinib (75 mg, orally BD), for a period of approximately 5 weeks. Selumetinib was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.
Placebo + RAI	Patients received placebo capsules (to match selumetinib, orally BD), for a period of approximately 5 weeks. Placebo was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.

Baseline Measures

	Selumetinib 75 mg BD + RAI	Placebo + RAI	Total
Number of Participants [units: Participants]	155	78	233
Age Continuous [units: Years] Mean ± Standard Deviation	46.2 ± 14.20	47.9 ± 14.67	46.8 ± 14.35
Sex: Female, Male [units: Participants]
Female	92	40	132
Male	63	38	101
Race/Ethnicity, Customized [units: Participants]
White	145	73	218
Black or African American	3	1	4
Asian	3	3	6
Other	4	1	5
Ethnicity (NIH/OMB) [units: Participants]
Hispanic or Latino	27	14	41
Not Hispanic or Latino	128	64	192
Unknown or Not Reported	0	0	0

Outcome Measures

1. Primary Outcome Measure: Complete remission rate (expressed as percentage of patients in complete remission) at 18 months post-RAI treatment; ITT analysis set [ Time Frame: At 18 months post-RAI treatment ]

Measure Type	Primary
Measure Name	Complete remission rate (expressed as percentage of patients in complete remission) at 18 months post-RAI treatment; ITT analysis set
Measure Description	Patients were defined to be in complete remission if all of the following criteria were demonstrated: 1. Serum thyroglobulin (Tg) levels <1 nanograms / millilitre (ng/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 ultrasound, as assessed by investigator site review. 3. No confirmed radiological evidence of thyroid cancer, as assessed by blinded independent central review. 4. No histopathological evidence of thyroid cancer on fine needle aspiration (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.
Time Frame	At 18 months post-RAI treatment
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The ITT analysis set included all randomised patients. Patients who were randomised but did not subsequently go on to receive selumetinib/placebo were included in the ITT analysis set.

Reporting Groups

	Description
Selumetinib 75 mg BD + RAI	Patients received selumetinib (75 mg, orally BD), for a period of approximately 5 weeks. Selumetinib was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.
Placebo + RAI	Patients received placebo capsules (to match selumetinib, orally BD), for a period of approximately 5 weeks. Placebo was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.

Measured Values

	Selumetinib 75 mg BD + RAI	Placebo + RAI
Number of Participants Analyzed [units:participants]	155	78
Complete remission rate (expressed as percentage of patients in complete remission) at 18 months post-RAI treatment; ITT analysis set [units: Percentage of participants]	40.0	38.5

Statistical Analysis 1 for Complete remission rate (expressed as percentage of patients in complete remission) at 18 months post-RAI treatment; ITT analysis set

Groups^[1]	All groups
Method^[3]	Regression, Logistic
P-Value^[4]	0.8205
Odds Ratio (OR)^[5]	1.07
95% Confidence Interval	( 0.61 to 1.87 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Selumetinib in combination with RAI was compared with placebo in combination with RAI. The analysis was performed using a logistic regression model including treatment as the only covariate. An odds ratio >1 favours selumetinib in combination with RAI.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	The primary endpoint was to be considered statistically significant if the 2-sided p-value was less than 0.05. P-value and confidence intervals (CIs) were calculated using profile likelihood.
[5]	Other relevant estimation information:
	No text entered.

2. Secondary Outcome Measure: Complete remission rate (expressed as percentage of patients in complete remission) at 18 months post-RAI treatment; subgroup analysis BRAF/NRAS mutation positive [ Time Frame: At 18 months post-RAI treatment ]

Measure Type	Secondary
Measure Name	Complete remission rate (expressed as percentage of patients in complete remission) at 18 months post-RAI treatment; subgroup analysis BRAF/NRAS mutation positive
Measure Description	Patients were defined to be in complete remission if all of the following criteria were demonstrated: 1. Serum Tg levels <1 ng/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 ultrasound, as assessed by investigator site review. 3. No confirmed radiological evidence of thyroid cancer, as assessed by blinded independent central review. 4. No histopathological evidence of thyroid cancer 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.
Time Frame	At 18 months post-RAI treatment
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The BRAF/NRAS mutation positive analysis set included only those patients from the ITT population whose tumour samples were mutation positive for the oncogenes BRAF or NRAS.

Reporting Groups

	Description
Selumetinib 75 mg BD + RAI	Patients received selumetinib (75 mg, orally BD), for a period of approximately 5 weeks. Selumetinib was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.
Placebo + RAI	Patients received placebo capsules (to match selumetinib, orally BD), for a period of approximately 5 weeks. Placebo was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.

Measured Values

	Selumetinib 75 mg BD + RAI	Placebo + RAI
Number of Participants Analyzed [units:participants]	91	51
Complete remission rate (expressed as percentage of patients in complete remission) at 18 months post-RAI treatment; subgroup analysis BRAF/NRAS mutation positive [units: Percentage of participants]	37.4	41.2

Statistical Analysis 1 for Complete remission rate (expressed as percentage of patients in complete remission) at 18 months post-RAI treatment; subgroup analysis BRAF/NRAS mutation positive

Groups^[1]	All groups
Method^[3]	Regression, Logistic
P-Value^[4]	0.6549
Odds Ratio (OR)^[5]	0.85
95% Confidence Interval	( 0.42 to 1.73 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Selumetinib in combination with RAI was compared with placebo in combination with RAI. The analysis was performed using a logistic regression model including treatment as the only covariate. An odds ratio >1 favours selumetinib in combination with RAI.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	P-value and CIs were calculated using profile likelihood.
[5]	Other relevant estimation information:
	No text entered.

3. Secondary Outcome Measure: Clinical remission rate (expressed as percentage of patients in clinical remission) at 18 months post-RAI treatment; ITT analysis set [ Time Frame: At 18 months post-RAI treatment ]

Measure Type	Secondary
Measure Name	Clinical remission rate (expressed as percentage of patients in clinical remission) at 18 months post-RAI treatment; ITT analysis set
Measure Description	Patients were defined to be in clinical remission if all of the following criteria were demonstrated: 1. Serum Tg levels <1 ng/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 ultrasound, as assessed by investigator site review. 3. No evidence of thyroid cancer on diagnostic whole body scan (WBS), as assessed by blinded independent central review. 4. No histopathological evidence of thyroid cancer on FNA/biopsy when performed to clarify equivocal ultrasound 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.
Time Frame	At 18 months post-RAI treatment
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The ITT analysis set included all randomised patients. Patients who were randomised but did not subsequently go on to receive selumetinib/placebo were included in the ITT analysis set.

Reporting Groups

	Description
Selumetinib 75 mg BD + RAI	Patients received selumetinib (75 mg, orally BD), for a period of approximately 5 weeks. Selumetinib was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.
Placebo + RAI	Patients received placebo capsules (to match selumetinib, orally BD), for a period of approximately 5 weeks. Placebo was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.

Measured Values

	Selumetinib 75 mg BD + RAI	Placebo + RAI
Number of Participants Analyzed [units:participants]	155	78
Clinical remission rate (expressed as percentage of patients in clinical remission) at 18 months post-RAI treatment; ITT analysis set [units: Percentage of participants]	40.0	38.5

Statistical Analysis 1 for Clinical remission rate (expressed as percentage of patients in clinical remission) at 18 months post-RAI treatment; ITT analysis set

Groups^[1]	All groups
Method^[3]	Regression, Logistic
P-Value^[4]	0.8205
Odds Ratio (OR)^[5]	1.07
95% Confidence Interval	( 0.61 to 1.87 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Selumetinib in combination with RAI was compared with placebo in combination with RAI. The analysis was performed using a logistic regression model including treatment as the only covariate. An odds ratio >1 favours selumetinib in combination with RAI.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	P-value and CIs were calculated using profile likelihood.
[5]	Other relevant estimation information:
	No text entered.

4. Secondary Outcome Measure: Clinical remission rate (expressed as percentage of patients in clinical remission) at 18 months post-RAI treatment; subgroup analysis BRAF/NRAS mutation positive [ Time Frame: At 18 months post-RAI treatment ]

Measure Type	Secondary
Measure Name	Clinical remission rate (expressed as percentage of patients in clinical remission) at 18 months post-RAI treatment; subgroup analysis BRAF/NRAS mutation positive
Measure Description	Patients were defined to be in clinical remission if all of the following criteria were demonstrated: 1. Serum Tg levels <1 ng/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 ultrasound, 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 ultrasound 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.
Time Frame	At 18 months post-RAI treatment
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The BRAF/NRAS mutation positive analysis set included only those patients from the ITT population whose tumour samples were mutation positive for the oncogenes BRAF or NRAS.

Reporting Groups

	Description
Selumetinib 75 mg BD + RAI	Patients received selumetinib (75 mg, orally BD), for a period of approximately 5 weeks. Selumetinib was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.
Placebo + RAI	Patients received placebo capsules (to match selumetinib, orally BD), for a period of approximately 5 weeks. Placebo was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.

Measured Values

	Selumetinib 75 mg BD + RAI	Placebo + RAI
Number of Participants Analyzed [units:participants]	91	51
Clinical remission rate (expressed as percentage of patients in clinical remission) at 18 months post-RAI treatment; subgroup analysis BRAF/NRAS mutation positive [units: Percentage of participants]	37.4	41.2

Statistical Analysis 1 for Clinical remission rate (expressed as percentage of patients in clinical remission) at 18 months post-RAI treatment; subgroup analysis BRAF/NRAS mutation positive

Groups^[1]	All groups
Method^[3]	Regression, Logistic
P-Value^[4]	0.6549
Odds Ratio (OR)^[5]	0.85
95% Confidence Interval	( 0.42 to 1.73 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Selumetinib in combination with RAI was compared with placebo in combination with RAI. The analysis was performed using a logistic regression model including treatment as the only covariate. An odds ratio >1 favours selumetinib in combination with RAI.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	P-value and CIs were calculated using profile likelihood.
[5]	Other relevant estimation information:
	No text entered.

Serious Adverse Events

Time Frame	Includes adverse events (AEs) with an onset date on or after the date of first dose and up to and including 30 days following the date of last dose of selumetinib/placebo. Overall timeframe for collection of AEs was up to 66 days from the first dose.
Additional Description	All-Cause Mortality is reported for the ITT analysis set for the overall study period. Serious and Other (non-serious) AE data is reported for the safety analysis set (including all patients who received at least 1 dose of randomised treatment) for the 5-week treatment period plus 30-day follow-up phase.

Reporting Groups

	Description
Selumetinib 75 mg BD + RAI	Patients received selumetinib (75 mg, orally BD), for a period of approximately 5 weeks. Selumetinib was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.
Placebo + RAI	Patients received placebo capsules (to match selumetinib, orally BD), for a period of approximately 5 weeks. Placebo was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.

Serious Adverse Events

Selumetinib 75 mg BD + RAI

Placebo + RAI

Total, serious adverse events

# participants affected / at risk

7/154 (4.55%)

0/77 (0.00%)

Immune system disorders

Drug hypersensitivity¹,^†

# participants affected / at risk

1/154 (0.65%)

0/77 (0.00%)

# events

Gastrointestinal disorders

Gastric haemorrhage¹,^†

# participants affected / at risk

1/154 (0.65%)

0/77 (0.00%)

# events

Infections and infestations

Cellulitis¹,^†

# participants affected / at risk

1/154 (0.65%)

0/77 (0.00%)

# events

Metabolism and nutrition disorders

Hypercalcaemia¹,^†

# participants affected / at risk

1/154 (0.65%)

0/77 (0.00%)

# events

Nervous system disorders

Syncope¹,^†

# participants affected / at risk

1/154 (0.65%)

0/77 (0.00%)

# events

Skin and subcutaneous tissue disorders

Dermatitis acneiform¹,^†

# participants affected / at risk

2/154 (1.30%)

0/77 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 21.1

Other Adverse Events

Time Frame	Includes adverse events (AEs) with an onset date on or after the date of first dose and up to and including 30 days following the date of last dose of selumetinib/placebo. Overall timeframe for collection of AEs was up to 66 days from the first dose.
Additional Description	All-Cause Mortality is reported for the ITT analysis set for the overall study period. Serious and Other (non-serious) AE data is reported for the safety analysis set (including all patients who received at least 1 dose of randomised treatment) for the 5-week treatment period plus 30-day follow-up phase.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Selumetinib 75 mg BD + RAI	Patients received selumetinib (75 mg, orally BD), for a period of approximately 5 weeks. Selumetinib was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.
Placebo + RAI	Patients received placebo capsules (to match selumetinib, orally BD), for a period of approximately 5 weeks. Placebo was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.

Other Adverse Events

Selumetinib 75 mg BD + RAI

Placebo + RAI

Total, other (not including serious) adverse events

# participants affected / at risk

141/154 (91.56%)

43/77 (55.84%)

Eye disorders

Periorbital oedema¹,^†

# participants affected / at risk

8/154 (5.19%)

0/77 (0.00%)

# events

Gastrointestinal disorders

Constipation¹,^†

# participants affected / at risk

15/154 (9.74%)

3/77 (3.90%)

# events

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

68/154 (44.16%)

12/77 (15.58%)

# events

Gastrointestinal disorders

Dry mouth¹,^†

# participants affected / at risk

15/154 (9.74%)

3/77 (3.90%)

# events

Skin and subcutaneous tissue disorders

Rash follicular¹,^†

# participants affected / at risk

13/154 (8.44%)

0/77 (0.00%)

# events

Nervous system disorders

Dysgeusia¹,^†

# participants affected / at risk

6/154 (3.90%)

4/77 (5.19%)

# events

Skin and subcutaneous tissue disorders

Rash macular¹,^†

# participants affected / at risk

12/154 (7.79%)

2/77 (2.60%)

# events

Eye disorders

Vision blurred¹,^†

# participants affected / at risk

16/154 (10.39%)

5/77 (6.49%)

# events

Gastrointestinal disorders

Dyspepsia¹,^†

# participants affected / at risk

8/154 (5.19%)

1/77 (1.30%)

# events

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

44/154 (28.57%)

8/77 (10.39%)

# events

Gastrointestinal disorders

Stomatitis¹,^†

# participants affected / at risk

17/154 (11.04%)

4/77 (5.19%)

# events

Gastrointestinal disorders

Vomiting¹,^†

# participants affected / at risk

14/154 (9.09%)

0/77 (0.00%)

# events

General disorders and administration site conditions

Face oedema¹,^†

# participants affected / at risk

9/154 (5.84%)

0/77 (0.00%)

# events

General disorders and administration site conditions

Fatigue¹,^†

# participants affected / at risk

44/154 (28.57%)

13/77 (16.88%)

# events

General disorders and administration site conditions

Oedema peripheral¹,^†

# participants affected / at risk

30/154 (19.48%)

4/77 (5.19%)

# events

Investigations

Blood creatine phosphokinase increased¹,^†

# participants affected / at risk

31/154 (20.13%)

1/77 (1.30%)

# events

Investigations

Weight decreased¹,^†

# participants affected / at risk

0/154 (0.00%)

4/77 (5.19%)

# events

Musculoskeletal and connective tissue disorders

Muscle spasms¹,^†

# participants affected / at risk

1/154 (0.65%)

4/77 (5.19%)

# events

Nervous system disorders

Headache¹,^†

# participants affected / at risk

8/154 (5.19%)

10/77 (12.99%)

# events

Nervous system disorders

Paraesthesia¹,^†

# participants affected / at risk

4/154 (2.60%)

4/77 (5.19%)

# events

Respiratory, thoracic and mediastinal disorders

Cough¹,^†

# participants affected / at risk

3/154 (1.95%)

4/77 (5.19%)

# events

Skin and subcutaneous tissue disorders

Acne¹,^†

# participants affected / at risk

13/154 (8.44%)

2/77 (2.60%)

# events

Skin and subcutaneous tissue disorders

Dermatitis acneiform¹,^†

# participants affected / at risk

67/154 (43.51%)

4/77 (5.19%)

# events

Skin and subcutaneous tissue disorders

Dry skin¹,^†

# participants affected / at risk

12/154 (7.79%)

4/77 (5.19%)

# events

Skin and subcutaneous tissue disorders

Pruritus¹,^†

# participants affected / at risk

21/154 (13.64%)

3/77 (3.90%)

# events

Skin and subcutaneous tissue disorders

Rash maculo-papular¹,^†

# participants affected / at risk

19/154 (12.34%)

4/77 (5.19%)

# events

Vascular disorders

Hypertension¹,^†

# participants affected / at risk

20/154 (12.99%)

3/77 (3.90%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 21.1

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: If the Study is part of a multi-centre clinical trial, the Institution or Investigator agree not to independently publish results of, or make presentations related to, the Study until first occurrence of one of the following: multi-centre primary Publication is published; no multi-centre primary Publication is submitted within 2 years after conclusion, abandonment or termination of the Study at all sites; or Sponsor confirms in writing there will be no multi-centre primary Publication.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
The study was terminated early (based on the findings of the primary analysis at 18 months post-RAI treatment) and all randomised patients who had not yet completed their 3-year follow-up visit were instead to have an end of study phone call.

Results Point of Contact

Name/Title:	Global Clinical Lead
Organization:	AstraZeneca
Phone	+1 302 885 1180
E-mail:	[email protected]

Documents available

Statistical Analysis Plan-edition 4_Redacted
Download
Redacted CSP
Download
https://filehosting-v2.pharmacm.com/api/Attachment/Download?tenantId=80217111&parentIdentifier=D1532C00065&attachmentIdentifier=49f06c23-25bc-4cde-bd5c-904895d052e2&fileName=Final-D1532C00065-Statistical_Analysis_Plan-edition_4_Redaction-checked-v1.0000.pdf&versionIdentifier=
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Contact Backup

AstraZeneca Cancer Study Locator Service

1-877-400-4656

Astrazeneca@emergingmed.com

Investigators

Principal Investigator

Alan Ho

Memorial Sloan Kettering Cancer Centre, 1275 York Avenue, New York, NY 10065.

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Statistical Analysis Plan-edition 4_Redacted

Redacted CSP

https://filehosting-v2.pharmacm.com/api/Attachment/Download?tenantId=80217111&amp;parentIdentifier=D1532C00065&amp;attachmentIdentifier=49f06c23-25bc-4cde-bd5c-904895d052e2&amp;fileName=Final-D1532C00065-Statistical_Analysis_Plan-edition_4_Redaction-checked-v1.0000.pdf&amp;versionIdentifier=

Trial Results Summaries

https://filehosting-v2.pharmacm.com/api/Attachment/Download?tenantId=80217111&parentIdentifier=D1532C00065&attachmentIdentifier=49f06c23-25bc-4cde-bd5c-904895d052e2&fileName=Final-D1532C00065-Statistical_Analysis_Plan-edition_4_Redaction-checked-v1.0000.pdf&versionIdentifier=